Pharmacology & Therapeutics 130 (2011) 348–363

Contents lists available at ScienceDirect

Pharmacology & Therapeutics

j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / p h a r m t h e r a

Associate editor: N. Frossard

Cytoplasmic dynein in neurodegeneration

Judith Eschbach a,b,c, Luc Dupuis a,b,⁎
a
Inserm U692, Laboratoire de Signalisations Moléculaires et Neurodégénérescence, Strasbourg, F-67085, France
b
Université de Strasbourg, Faculté de Médecine, UMRS692, Strasbourg, F-67085, France
c
Department of Neurology, University of Ulm, Germany

a r t i c l e i n f o a b s t r a c t

Keywords: Cytoplasmic dynein 1 (later referred to as dynein) is the major molecular motor moving cargoes such as
Axonal transport mitochondria, organelles and proteins towards the minus end of microtubules. Dynein is involved in multiple
Microtubules basic cellular functions, such as mitosis, autophagy and structure of endoplasmic reticulum and Golgi, but also
Molecular motor in neuron specific functions in particular retrograde axonal transport. Dynein is regulated by a number of
Amyotrophic lateral sclerosis protein complexes, notably by dynactin. Several studies have supported indirectly the involvement of dynein
Alzheimer's disease
in neurodegeneration associated with Alzheimer's disease, Parkinson's disease, Huntington's disease and
Huntington's disease
motor neuron diseases. First, axonal transport disruption represents a common feature occurring in
neurodegenerative diseases. Second, a number of dynein-dependent processes, including autophagy or
clearance of aggregation-prone proteins, are found defective in most of these diseases. Third, a number of
mutant genes in various neurodegenerative diseases are involved in the regulation of dynein transport. This
includes notably mutations in the P150Glued subunit of dynactin that are found in Perry syndrome and motor
neuron diseases. Interestingly, gene products that are mutant in Huntington's disease, Parkinson's disease,
motor neuron disease or spino-cerebellar ataxia are also involved in the regulation of dynein motor activity or
of cargo binding. Despite a constellation of indirect evidence, direct links between the motor itself and
neurodegeneration are few, and this might be due to the requirement of fully active dynein for development.
Here, we critially review the evidence of dynein involvement in different neurodegenerative diseases and
discuss potential underlying mechanisms.
© 2011 Elsevier Inc. All rights reserved.

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 348
2. Cytoplasmic dynein: structure and function . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 349
3. Potential consequences of dynein dysfunction and their links to neurodegeneration . . . . . . . . . . . . 349
350
4. Cytoplasmic dynein in motor neuron diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 349
351
5. Cytoplasmic dynein in basal ganglia degeneration . . . . . . . . . . . . . . . . . . . . . . . . . . . . 350
353
6. Cytoplasmic dynein in Alzheimer's disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 350
355
7. Cytoplasmic dynein in other neurodegenerative diseases . . . . . . . . . . . . . . . . . . . . . . . . . 350
356
8. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 351
357
Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 351
358
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 352
358

Abbreviations: AD, Alzheimer's disease; ALS, amyotrophic lateral sclerosis; AR,
androgen receptor; CMT, Charcot–Marie–Tooth disease; FAT, fast axonal transport;
FTD, fronto-temporal dementia; HAP-1, huntingtin associated protein 1; HD, Hunting-
ton's disease; HTT, huntingtin; MND, motor neuron disease; NDD, Neurodegenerative
disease; PD, Parkinson's disease; SBMA, spinal and bulbar muscular atrophy (Kennedy's
disease); SCA, spino-cerebellar ataxia; SMA, spinal muscular atrophy.
⁎ Corresponding author at: INSERM U692, Faculté de Médecine, bat 3, 8e étage, 11 rue
Humann, STRASBOURG, F-67085, France. Tel.: +33 3 68853091; fax: +33 3 68853065.
E-mail address: ldupuis@unistra.fr (L. Dupuis).
1. Introduction
Neurodegenerative diseases (NDDs) are a large and diverse group
of pathologies characterized by the degeneration of a subset of
neurons. NDDs include very frequent pathologies of the elderly, such
as Alzheimer's disease (AD) which concerns about 20 to 25 million
persons worldwide, or Parkinson's disease (PD), with an incidence
between 16 and 20 per 100,000. A number of NDDs are much less

0163-7258/$ – see front matter © 2011 Elsevier Inc. All rights reserved.
doi:10.1016/j.pharmthera.2011.03.004
 J. Eschbach, L. Dupuis / Pharmacology & Therapeutics 130 (2011) 348–363
frequent with incidences ranging from 2 to 3 per 100,000 for
amyotrophic lateral sclerosis (ALS) to a few cases worldwide for the
rarest NDDs. NDDs can be either inherited or appear sporadically in
non-previously affected families. Indeed, a number of NDDs are
monogenic diseases (HD for instance) with dominant or recessive
transmission patterns. However, for the most frequent NDDs (AD, PD,
and ALS), there are only rare familial cases, but a majority of sporadic
cases, with currently unknown causes. The socio-economic burden of
NDDs is strongly increasing in western countries, mostly because a
number of the most frequent NDDs are associated with aging, the
current increase in lifespan thus mechanically leading to increased
frequencies of NDDs.
The common point to all NDDs is the occurrence of neuronal
degeneration. This degenerative phenotype covers several distinct
events that include disappearance of cell bodies but also shrinkage of
axonal or dendritic compartments. Indeed, it appears that the symp-
toms of a number of NDDs are caused by loss of synaptic connections
rather than loss of neuronal cell bodies themselves (Dupuis & Loeffler,
2009; Palop & Mucke, 2010; van Spronsen & Hoogenraad, 2010). The
very different symptoms elicited by NDDs are caused by the nature of
the affected neurons: the degeneration might be widespread like in
prion diseases for instance, or affect only a small neuronal population,
with consequences limited to functions controlled by this neuronal
subset. This is for instance the case in PD, in which the primarily
affected cells are dopaminergic neurons from the substantia nigra.
These neurons are involved in the fine tuning of movement initiation
and their degeneration leads to tremor and bradykinesia. This initial
cell selectivity remains however relative. Indeed, it is increasingly
recognized that despite this apparent starting point, degeneration
involves a number of other cell types (Boillee et al., 2006; Dupuis &
Loeffler, 2009; Dupuis & Echaniz-Laguna, 2010).
There are a number of common themes between NDDs. The most
salient pathological feature of NDDs is the occurrence of protein
aggregates (Cuervo et al., 2010; Krainc, 2010). Among the different
NDDs, these aggregates might be either intracellular, such as AD-
associated neurofibrillary tangles or extracellular such as amyloid
plaques in AD. The biochemical composition of protein aggregates are
also differing between NDDs, and are most often revealing underlying
pathogenic pathways (Neumann et al., 2006; Kabashi et al., 2008;
Sreedharan et al., 2008; Crews & Masliah, 2010). A second theme
common to almost all NDDs is that neuronal degeneration is not cell
autonomous, meaning that neuronal degeneration is due to events
both intrinsic and extrinsic to neurons (Ilieva et al., 2009). A third
mechanism appears common to most NDDs: axonal transport
impairment. Exchange of cargoes between the neuronal cell body
and the axonal tip is called axonal transport. Long distance transport is
carried out on microtubules, while short distance appears mediated
by the actin cytoskeleton. Microtubules constitute the railroad tracks
on which molecular motors are able to carry cargoes from the cell
body to the synapse (anterograde axonal transport) or from the
synapse to the cell body (retrograde axonal transport). Anterograde
axonal transport is carried out by kinesin like motors, while
retrograde axonal transport is performed mostly by a single motor,
cytoplasmic dynein. A large body of evidence has demonstrated that
axonal transport machinery is impaired during neurodegeneration,
and likely contributes to it (Chevalier-Larsen & Holzbaur, 2006; De
Vos et al., 2008; Morfini et al., 2009).
In this review, we will focus on one major actor involved in these
different common themes in NDDs. Cytoplasmic dynein is the major
motor of retrograde axonal transport (Levy & Holzbaur, 2006). As
such, the impairment of its function appears able to lead to axonal
transport dysfunction. Cytoplasmic dynein is also the molecular
motor responsible for transport of misfolded proteins for their
degradation, and is thus crucially involved in the appearance and
clearance of protein aggregates. Last, dynein is the molecular motor
responsible for retrograde signalling from the synapse to the cell
349
body. This mechanism is involved in cell to cell communication in the
nervous system and its dysfunction might account for non cell
autonomy of neuronal death in NDDs. Cytoplasmic dynein is thus at a
nexus of various pathophysiological mechanisms in NDDs. Here, we
will first review the structure of the molecular motor and the
potential consequences of its dysfunction. We will then critically
review the evidence that involve directly or indirectly dynein in
neurodegenerative diseases, such as motor neuron diseases (includ-
ing ALS), basal ganglia degeneration (mostly HD and PD) and
dementia (including AD).
2. Cytoplasmic dynein: structure and function
2.1. Cytoplasmic dynein, a retrograde motor
Dyneins are a large group of molecular motors that include
multiple axonemal motors (axonemal dyneins) and two complexes
termed “cytoplasmic dynein”. Dynein motors are very different in
their structures, localizations and functions (Pfister et al., 2005, 2006),
and we will here focus on cytoplasmic dynein 1. Indeed, despite there
are two molecular complexes called “cytoplasmic dynein” (cytoplas-
mic dyneins 1 and 2), cytoplasmic dynein 2 appears mostly present in
ciliated cells and is involved in intraflagellar transport, at least in
lower eukaryotes (Porter et al., 1999). The expression pattern of
cytoplasmic dynein 2 is consistent with this view (Mikami et al.,
2002). Despite the recent discovery of human mutations in the heavy
chain of cytoplasmic dynein 2 (Dagoneau et al., 2009), little is known
about cytoplasmic dynein 2 function in mammals.
Cytoplasmic dynein 1 (later referred as dynein in this review) is
expressed in most tissues, including brain, testis, lung, liver and
kidney (Yoshida et al., 1992) and is involved in the transport of
cargoes on microtubules, from the periphery to the cell center in a
process called “retrograde transport”. Dynein, initially named MAP1C,
was discovered in 1987 (Paschal et al., 1987) and was initially identi-
fied as a component of microtubule preparations. Dynein was shown
to possess ATP-hydrolyzing activity and microtubule translocation
properties (Paschal et al., 1987) and to be able to produce force in a
direction opposite to that observed for kinesin-1, suggesting that it
constituted a retrograde motor (Paschal & Vallee, 1987). Later work
has shown that dynein is able to move cargoes using variable step
sizes, but also lateral steps across the microtubule surface, and
processive runs toward both the minus- and plus-end of the micro-
tubule (Mallik et al., 2004; Ross et al., 2006). ATP-binding activity is
localized on the C-terminal two-thirds of the dynein heavy chain
protein (Gee et al., 1997) and is due to the presence of six tandemly
AAA (ATPase associated with cellular activities) modules necessary
for ATP hydrolysis (Takahashi et al., 2004). The dimerization of two
dynein heavy chains is necessary for motor activity. The two globular
heads contain in their C-terminus the motor domain, where ATP is
hydrolyzed to produce the strength necessary for dynein displace-
ment along the microtubules, and the microtubule-binding site which
is localized between the AAA4 and AAA5. The tail domain, located at
the N-terminus of dynein heavy chain, is involved in the dimerization
of the two heavy chains (Hirokawa et al., 2010).
2.2. Cytoplasmic dynein structure
Apart from the two heavy chains of 530 kD (Paschal et al., 1987;
Holzbaur & Vallee, 1994), that constitute the motors themselves,
dynein is a multi complex protein composed of a number of non-
catalytic subunits, notably two intermediate chains of 74 kD, and four
light intermediate chains of 55 kD and a number of less characterized
light chains such as LC8, Tctex1 or Rp3 (King et al., 1998; Hirokawa
et al., 2010).
The tail domain of dynein heavy chain interacts with intermediate
light and light chains to form the cargo-binding complex. The accessory
350 J. Eschbach, L. Dupuis / Pharmacology & Therapeutics 130 (2011) 348–363

proteins of the dynein complex are probably crucial in the cargo selec-
tivity of the motor (Kardon & Vale, 2009) (Fig. 1).
2.3. Regulation of dynein activity
Dynein activity requires a number of other proteins. Indeed,
dynein is associated with dynactin (Karki & Holzbaur, 1995; Vaughan
& Vallee, 1995), another multi-protein complex with ten subunits
including P150Glued, p135Glued, p62, p50 (dynamitin) and Arp1
(Schroer, 2004) (Fig. 1). Dynactin interacts with dynein through
dynein intermediate chain and p150Glued (Vaughan, 2005). Dynactin
was first shown to be required for cargo binding (Karki & Holzbaur,
1995; Vaughan & Vallee, 1995; Schroer, 2004). In particular, the Arp1
subunit of dynactin binds to β-III spectrin a filamentous protein that is
found on the cytosolic side of a number of intracellular vesicles
(Holleran et al., 2001) (Fig. 1). A second function of dynactin is to
increase dynein processivity (King & Schroer, 2000). Despite these
multiple roles of dynactin, how these different dynactin functions are
integrated remains largely unknown.
Dynein activity is modulated by a number of ubiquitous cofactors
such as UNC-83 (Fridolfsson et al., 2010), LIS1-Ndel1-Nde1 and
Bicaudal-D (see for review (Dienstbier & Li, 2009) that have been
reviewed elsewhere (Kardon & Vale, 2009). More recently, multiple
evidence point to a regulation of motor activities, and in particular of
dynein, by signalling pathways, notably by kinases. First, dynein has
been shown to interact with huntingtin and huntingtin-associated
protein 1 (Caviston et al., 2007) and Akt mediated phosphorylation of
huntingtin is able to promote anterograde transport through kinesin-
1 recruitment, while dephosphorylation of huntingtin stimulates
dynein dependent retrograde transport (Colin et al., 2008). Thus,
huntingtin and HAP-1 appear to integrate the different directions of
transport. Other kinases are likely involved in the regulation of dynein
activity. Indeed, two cyclin dependent kinases, CDK-5 and PCT-1 and
the cyclin CCY-1 have been shown to negatively regulate dynein in the
nematode (Ou et al., 2010) and the JNK kinase pathway might also be
involved in the regulation of dynein (Morfini et al., 2006).
2.4. A motor with multiple functions
Dynein has a large variety of functions and is involved in a number
of different cell processes. The most well documented function is the
minus end-directed transport of membranous organelles (Schroer
et al., 1989). In neurons, dynein is responsible for retrograde axonal
transport (Schnapp & Reese, 1989). Dynein is able to transport a large
variety of cargoes such as mitochondria, proteins (neurofilaments,
trophic factors like brain-derived neurotrophic factor, RNA particles
(see for review (Chevalier-Larsen & Holzbaur, 2006)). Dynein also
participates in endoplasmic reticulum membrane tubules organisation
(Terasaki, 1990), is required in vitro for the formation of endoplasmic
reticulum networks (Allan, 1995), and for the centrosomal localization
of the Golgi complex (Corthesy-Theulaz et al., 1992). Dynein maintains
the microtubule networks (Ross et al., 2008a) and is involved in the
lysomal trafficking (Lin & Collins, 1992), and in the vesicular transport
from early to late endosomes (Aniento et al., 1993). Dynein is also
involved in the clearance of protein aggregates since mutation in
dynein impairs their autophagic clearance (Ravikumar et al., 2005).
Dynein is required for mitosis since it was found on kinetochores (Pfarr
et al., 1990) and drives them to the spindle poles (Hoogenraad et al.,
2001; Matanis et al., 2002). Dynein is also able to drive lipid droplets
(Gross et al., 2000), participates indirectly in their formation (Bostrom
et al., 2005; Andersson et al., 2006; Bostrom et al., 2007) and break-
down (Eschbach et al., 2011).
3. Potential consequences of dynein
dysfunction and their links to neurodegeneration
Given the very large requirement for dynein in many basic cell
processes, a number of dynein functions have been, directly or
indirectly, linked with NDDs. First, dysfunction in dynein transport
was long associated with decreased retrograde axonal transport (Levy
& Holzbaur, 2006). This decreased transport has potentially two
consequences: first, it is expected to decrease the transport of
organelles back to the cell body. This has been especially studied for
axonal transport of mitochondria and dynein and kinesin-1 constitute

Fig. 1. Schematic representation of dynein–dynactin complex. Dynein–dynactin complex drive cargoes along microtubules from theirs minus ends toward theirs plus ends. Dynein is
a large, multimeric protein complex composed of two heavy chains, three intermediate chains, four light intermediate chains (not represented) and light chains. Dynactin, which
increases dynein processivity, is itself a large protein complex, with numerous subunits, including P150Glued, p135Glued, p62, p50 (dynamitin), Arp1, p27, p24 and actin capping
protein. Attachment of cargoes to dynein–dynactin complex requires the interaction with β3-Spectrin, ankyrin (not represented) and Arp1 (a dynactin subunit).
 J. Eschbach, L. Dupuis / Pharmacology & Therapeutics 130 (2011) 348–363 351

the major motors for fast axonal transport of mitochondria (Hollen-
beck & Saxton, 2005; Pilling et al., 2006; Frederick & Shaw, 2007)
(Fig. 2). However, the exact consequences of decreased retrograde
transport on mitochondrial bioenergetic functions remain unex-
plored. Second, decreased retrograde axonal transport should also
lead to decreased retrograde signalling through decreased transport
of signalling endosomes (Fig. 2). Indeed, axonal injury activates a
number of signalling events that lead to transport signal to the
nucleus through dynein dependent processes (Delcroix et al., 2003;
Heerssen et al., 2004; Yudin et al., 2008; Rishal & Fainzilber, 2010).
More generally, synaptogenesis and synaptic maintenance are largely
driven by retrograde messengers (Regehr et al., 2009). This is espe-
cially true for neurotrophin retrograde signalling that is completely
dependent upon the formation of signalling endosomes carried to the
cell body by dynein (Heerssen et al., 2004; Mallik & Gross, 2004;
Zweifel et al., 2005; Cosker et al., 2008).
Besides axonal transport, dynein dysfunction might impact
general neuronal physiology. First, dynein is critically involved in
intracellular membranes trafficking. For instance, dynein is required
for endosomal and lysosomal transport (Hirokawa, 1998; Mallik &
Gross, 2004) (Fig. 2). Indeed, both dynein and endosomal transport
are required for dendritic morphogenesis (Satoh et al., 2008; Zheng
et al., 2008; Braunstein et al., 2010). This role of dynein in dendritic
morphogenesis is thought to be linked to dynein role in retrograde
movement of neurofilaments (Wagner et al., 2004). Second, disrup-
tion of endosomal trafficking might lead to abnormal autophagic
vesicle trafficking (Ravikumar et al., 2005; Jahreiss et al., 2008)
(Fig. 2). Third, signalling events might also be affected by abnormal
trafficking of endo-lysosomal membranes. For instance, cholesterol
sensing in cells requires endosomal trafficking and is dynein
dependent (Johansson et al., 2007; Rocha et al., 2009). Dynein
dysfunction might thus also affect transduction pathways in response
to environmental cues. Last, dynein interacts with HDAC6 and this is
required for the formation of aggresome (Kawaguchi et al., 2003;
Zhou et al., 2009) a subcellular structure located at the microtubule
organising center and required for misfolded protein clearance
(Fig. 2).
In the specific context of NDDs, dynein dysfunction is generally
considered as a pathogenic event in post-mitotic neurons. However,
dynein is also crucial for mitosis and through its function in mitotic
spindle orientation, dynein appears critically involved in neurogen-
esis (Zhang et al., 2009; Godin et al., 2010). Impairment of dynein
function at adult age might thus also decrease neurogenesis and have
an impact on cognition.
Dynein is thus involved in multiple pathways relevant to NDDs
pathogenesis (Fig. 2). It should be noted that a number of these dynein
dependent processes have been studied in the context of develop-
ment, but not necessarily in the context of neurodegeneration.
4. Cytoplasmic dynein in motor neuron diseases
4.1. Motor neuron diseases
Motor neuron diseases are a group of heterogenous pathologies
that all involve degeneration of the lower motor neurons, and a
relative sparing of sensory innervation. Among MNDs, ALS, spinal
muscular atrophy (SMA) and spino-bulbar muscular atrophy (SBMA)
are the most frequent (Brooks et al., 2000).
Childhood spinal muscular atrophy (hereafter called spinal
muscular atrophy, SMA) is a child-onset motor neuron disease
involving mutations in the survival of motor neuron gene (smn1)
(Lefebvre et al., 1995). SMA patients are divided in three clinical
groups according to the severity of their disease, with type I SMA
being the most severe form leading to death before two years of age
and type III SMA the less severe form with muscle weakness starting
after 18 months of age. SMA is caused by mutations in the SMN1 gene
and the severity of the disease is linked to the potential compensation
by SMN2 protein products.
Spinal and bulbar muscular atrophy (SBMA), or Kennedy's disease,
is a monogenic motor neuron disease caused by expansion of a CAG
repeat in the first exon of the androgen receptor (AR) gene (La Spada
et al., 1991). This leads to an AR protein with an expanded polygluta-
mine (polyQ) tract only in individuals bearing an expansion of the

Fig. 2. Dynein functions relevant to neurodegenerative diseases. Dynein is involved in basic cellular functions (general, right of the figure) and axonal transport related functions (left
of the figure). Dynein is responsible for retrograde axonal transport of organelles, including mitochondria (1), and for transport of signaling endosomes (2) that convey signals of
neurotrophins. Dynein is responsible for multiple transport of organelles in the cell body, for instance autophagosomes (3) and ER-to-Golgi transport (4). In neurons, dynein is
required for dendrite morphogenesis through still incompletely understood mechanisms (5). Last, dynein is responsible for the transport of misfolded proteins in the aggresome (6).
352 J. Eschbach, L. Dupuis / Pharmacology & Therapeutics 130 (2011) 348–363
polyQ tract over 36 glutamines. SBMA is an X-linked, gender specific
disease since only male carriers of a pathogenic mutation are affected.
Amyotrophic lateral sclerosis (ALS) is the most frequent motor
neuron disease of adult onset. In ALS, not only lower motor neurons
degenerate, but also upper motor neurons (corticospinal motor
neurons). The prognosis of ALS is very poor with death generally
occurring two to five years after the diagnosis. A subset of ALS cases
(20%) are inherited (familial ALS), but the vast majority of ALS cases
remain of unknown origin. Several genes including angiogenin
(Greenway et al., 2006), vapb (Nishimura et al., 2004), and more
recently tardbp (encoding TDP43) (Kabashi et al., 2008; Kuhnlein
et al., 2008; Rutherford et al., 2008; Sreedharan et al., 2008; Yokoseki
et al., 2008), fus (Kwiatkowski et al., 2009; Ticozzi et al., 2009) and fig4
(Chow et al., 2009) have been genetically linked to familial forms of
ALS, but how these specific mutations lead to ALS is currently
unknown (Lagier-Tourenne & Cleveland, 2009). On the contrary, the
mechanisms underlying ALS linked to mutations in the sod1 gene, the
first gene linked to familial ALS in 1993, have been extensively studied
(Boillee et al., 2006; Gonzalez de Aguilar et al., 2007; Dupuis &
Loeffler, 2009).
4.2. Indirect evidence of dynein involvement in motor neuron diseases
A number of cellular functions involving dynein appear impaired
in MNDs. First, a large body of literature documented abnormalities in
axonal transport. The possibility that axonal transport defects
participate in motor neuron disease pathology stems from observa-
tions of axonal swellings in pathological images of ALS motor neurons.
For instance, Binet & Meininger (1988) observed abnormalities in
cytoskeletal proteins such as tubulin in otherwise pathologically
normal axons and Breuer et al. (1987) observed increased antero-
grade and decreased retrograde axonal transport in nerves of ALS
patients. Sasaki & Iwata (1996) observed a marked increase in
mitochondria and lysosomes in the proximal axon of ALS patients,
suggesting that these organelles were not properly targeted in the
axon possibly due to fast axonal transport impairment. Analysis in
animal models have shown impairments of both fast and slow axonal
transport, very early in the disease process and in both directions
(Zhang et al., 1997; Williamson & Cleveland, 1999; Sasaki et al., 2005;
De Vos et al., 2007; Perlson et al., 2009; Shi et al., 2010). Similar
evidence have been obtained in animal models of SBMA (Katsuno
et al., 2006), thus suggesting that impairment in axonal transport is a
general feature of MNDs. In all, available evidence strongly indicate
that axonal transport is compromised in both directions in motor
neuron disease.
Other pathological hallmarks of MNDs indirectly indicate an
involvement of dynein in MNDs. First, MNs from ALS patients display
a very pronounced fragmentation of the Golgi apparatus and the
endoplasmic reticulum (ER) (Gonatas et al., 2006). Analogous pictures
are observed in vitro and in vivo after disruption of dynein either by
knock-out, siRNA, dynamitin overexpression or mutant p150glued
overexpression (Burkhardt et al., 1997; Harada et al., 1998; Caviston
et al., 2007; Chevalier-Larsen et al., 2008; Laird et al., 2008). Second,
MNs from ALS patients display a number of protein aggregates that
are mostly ubiquitin positive, and include TDP43 as the major protein
aggregated (Deng et al., 2010). Mutant proteins linked to ALS, such as
mutant forms of SOD1 or TDP43, misfold, aggregate and impair the
activity of the proteasome. Since dynein is in general required to
achieve clearance of misfolded proteins, dynein activity is a potential
modulator of protein aggregation in ALS.
4.3. Genetic evidence of dynein involvement in MNDs
4.3.1. Dynactin mutations in MNDs
Mutations in the dynein heavy chain do not appear to cause
MNDs (Ahmad-Annuar et al., 2003), but a number of indirect genetic
evidence also point to dynein as key to MNDs pathogenesis. First,
mutations in the dynactin P150glued have been documented in familial
cases of ALS and distal SBMA, a rare MND (Puls et al., 2003; Munch
et al., 2004; Puls et al., 2005). One of these mutant proteins bearing
the G59S mutation, impairs dynein/dynactin function (Levy et al.,
2006) and, when overexpressed in transgenic mice, the G59S
mutation in p150Glued leads to enlarged lysosomes, accumulation of
vesicles and distal degeneration of neuromuscular junctions (Lai et al.,
2007; Chevalier-Larsen et al., 2008; Laird et al., 2008). However, only
one of these three mouse strains displayed frank paralysis and
shortened survival (Laird et al., 2008), while the other two mouse
strains did not progress to paralysis. Furthermore, it appears that
G59S overexpression is not sufficient to impair retrograde axonal
transport, which suggests that other functions of the dynein/dynactin
complex, including clearance of protein aggregates are instrumental
in the mild pathology of these mice (Levy et al., 2006).
4.3.2. Other dynein-related genes linked to MNDs
Other genetic mutations linked to ALS are likely to alter dynein
function. First, mutations in the GTP exchange factor alsin were
observed in atypical juvenile forms of motor neuron diseases mostly
affecting the upper motor neuron (Hadano et al., 2001; Yang et al.,
2001). These mutations were called ALS2 and later found also in
families with typical hereditary spastic paraplegia (HSP) (Eymard-
Pierre et al., 2002). Alsin functions as a promoter of Rab5 activity and
regulates endolysosomal trafficking (Otomo et al., 2003; Topp et al.,
2004; Devon et al., 2006; Hadano et al., 2006). Whether ALS2
mutations directly or indirectly affect dynein activity is still to be
studied (Fig. 3).
Mutations in a component of the endosomal sorting complex
(ESCRT) CHMP2B have been found in ALS and fronto-temporal
dementia (FTD) (Skibinski et al., 2005; Parkinson et al., 2006; Cox
et al., 2010). The ESCRT complex is required for the transport of
membrane proteins to multivesicular bodies. Furthermore, FTD-
related mutations in CHMP2B perturb endosomal trafficking (van
der Zee et al., 2008; Urwin et al., 2010). The mutations in CHMP2B lead
to protein aggregates through compromised autophagy and impair
clearance of mutant TDP43 (Filimonenko et al., 2007). The involve-
ment of dynein in these events has not been investigated but is likely
since transport to MVBs is dynein dependent (Lee et al., 2007; Saksena
et al., 2007; Hurley, 2008; Raiborg & Stenmark, 2009; Stuffers et al.,
2009) (Fig. 3).
Mutations in the gene encoding for the VAPB protein have been
linked with familial forms of ALS and have been termed als8/VAPB
(Nishimura et al., 2004). A mutation (P56S) in the VAPB gene has been
reported in a Brazilian pedigree of Portuguese origin, but also in two
others unrelated families (Funke et al., 2010; Millecamps et al., 2010).
Another mutation (T46I) in a British family has been recently
described (Chen et al., 2010). There exists a phenotypic variability
between als8 patients ranging from pure typical ALS (both upper
motor neuron and lower motor neuron involvement) to late onset
SMA (lower motor neuron only involvement). In some instances,
autonomic dysfunction has been observed (Nishimura et al., 2004;
Marques et al., 2006). However, in all patients reported to date, there
is an involvement of lower motor neuron, progressing, or not, to both
lower motor neuron and upper motor neuron involvement. Thus,
als8-linked pathologies are either pure ALS or pathologies close to
ALS. VAPB is one of the members of the VAP family of proteins which
are binding partners of VAMP/synaptobrevin. VAPB is an integral
membrane protein localized to the endoplasmic reticulum and Golgi
intermediates. VAPB has been shown to modulate dynein dependent
transport through its interactions with lipid-binding proteins carrying
a FFAT motif (Peretti et al., 2008; Raychaudhuri & Prinz). Among FFAT
motif containing proteins and VAPB interaction partners, the
oxysterol binding protein family (OSBPs) directly bind to cholesterol
and its oxidized derivatives (Raychaudhuri & Prinz). One OSBP, ORP1L
 J. Eschbach, L. Dupuis / Pharmacology & Therapeutics 130 (2011) 348–363 353

Fig. 3. Dynein involvement in motor neuron diseases. P150Glued, a component of the dynactin complex is mutated in some familial MND cases and overexpression of dynamitin in
mouse leads to motor neuron disease. Mutant androgen receptor (linked to SBMA) and variants of Elp3, associated with ALS, impact dynein activity indirectly. Last, mutations in
genes that modulate dynein activity in endosomal trafficking, such as VAPB, CHMP2B or ALS2 were found in familial ALS cases. Gene mutants in MNDs or associated with MNDs are
indicated by dark grey circles.

is found in late endosomes and has recently been found to be sensor of expanded AR, is directly responsible for the modulation of dynein
intracellular cholesterol levels (Rocha et al., 2009). ORP1L binds to activity remains unclear.
VAPB in conditions of low cholesterol, and this leads to removal of
dynein and dynactin from late endosomes, inhibiting their perinuclear
4.5. Conclusion
transport and the subsequent cellular responses to cholesterol (Rocha
et al., 2009). Thus, VAPB is a master regulator of endosomal transport
In all, despite a striking amount of knowledge on the involvement
and dynein function (Fig. 3).
of axonal transport and endosomal trafficking, most definitive
Last, variants in Elongator protein 3(Elp3), a component of the
evidence linking dynein to MNDs are indirect. Genetic mutations
Elongator protein complex, have been associated in one study with
leading to MNDs affect modulators of dynein function, while most
sporadic ALS (Simpson et al., 2009). Elongator, among other functions,
experimental evidence used overexpression of interaction partners.
promotes tubulin acetylation through the acetyl transferase activity of
For instance, disrupting dynein function through the overexpression
Elp3 (Creppe et al., 2009). Tubulin acetylation promotes anchoring of
of dynamitin or of Bicaudal D2, leads not only to dynein/dynactin
dynein to microtubules and facilitates dynein mediated transport. It
interaction disruption but also to mild motor neuron degeneration
was proposed that the dysfunction in tubulin acetylation triggered by
(LaMonte et al., 2002; Teuling et al., 2008). Furthermore, over-
Elp3 variants would decrease dynein mediated transport, leading to
expression of mutant p150Glued disrupted endosomal trafficking, led
neurodegeneration (Nguyen et al., 2010) (Fig. 3). Further work is
protein aggregation and cell death (Levy et al., 2006; Lai et al., 2007;
clearly needed to ascertain this working hypothesis.
Chevalier-Larsen et al., 2008; Laird et al., 2008) (Fig. 3). Nevertheless,
Thus, dynein involvement in MNDs is indirectly suggested by the
the use of such interaction partners to study dynein function is
occurrence of several mutations in modulators of some dynein-
uncertain due to their probable or demonstrated dynein independent
dependent transport events, including dynactin, CHMP2B, VAPB, ELP3
functions. Two mutations in the dynein heavy chain gene have been
and ALS2. However there are currently no direct evidence linking
identified in mutant mouse strains. These mutations appear to
genetically dynein and MNDs.
decrease the processivity of the mutant, which might underlie the
relatively benign phenotype of heterozygous mice (Ori-McKenney
et al., 2010). Dynein mutant mice have been initially thought to lead
4.4. Potential mechanisms underlying dynein involvement in MNDs
to motor neuron disease (Hafezparast et al., 2003) on the basis of
abnormal reflexes and potential motor neuron loss. However, three
How pathogenic mechanisms leading to MNDs might lead to
laboratories failed to reproduce the observation of motor neuron loss
dynein dysfunction remains unclear. A couple of studies have
and on the contrary showed that dynein mutant mice displayed
suggested that mutant forms of SOD1 directly bind to dynein and
proprioceptive sensory neuropathy (Chen et al., 2007; Ilieva et al.,
that this interaction was responsible for SOD1 aggregation (Zhang
2008; Dupuis et al., 2009). Thus, up to now, there currently lacks
et al., 2007; Strom et al., 2008). Furthermore, mutant SOD1 over-
direct evidence of dynein involvement in MNDs.
expression altered dynein and dynactin localization, suggesting that
mutant SOD1 led to dynein dysfunction (Ligon et al., 2005). Recent
work however failed to reproduce the direct interaction between 5. Cytoplasmic dynein in basal ganglia degeneration
mutant SOD1 and dynein (El-Kadi et al., 2010), and if existing, this
direct interaction might be non specific due to the transport of 5.1. Basal ganglia diseases
misfolded proteins by dynein to degradation. To our knowledge, there
is currently no study linking other causes of ALS such as TDP43 or FUS Basal ganglia are a group of subcortical structures that includes the
mutations to dynein. striatum, the globus pallidus, substantia nigra and subthalamic nuclei.
The picture appears clearer for SBMA. Indeed, Brady and Although heterogeneous, these structures are all involved in senso-
colleagues have demonstrated that the expanded polyQ AR was able rimotor functions and in particular in the selection, planning and
to inhibit both anterograde and retrograde axonal transport in initiation of voluntary movements. Basal ganglia are highly inter-
isolated squid axoplasm (Szebenyi et al., 2003). This effect was later connected with other brain structures, notably the thalamus and the
shown to be dependent upon the JNK pathway (Morfini et al., 2006), cortex, and are involved in neural circuits called basal ganglia loops
although whether increased JNK activity, as elicited by the polyQ (cortico-basal ganglia-thalamo-cortical loops) whose dysfunction
354 J. Eschbach, L. Dupuis / Pharmacology & Therapeutics 130 (2011) 348–363
leads to motor disorders. (See for reviews: (Alexander et al., 1990;
Middleton & Strick, 2000)).
For instance, Parkinson's disease (PD), the most frequent disease of
basal ganglia, is due to the selective loss of dopamine neurons in the
substantia nigra. These neurons are involved in the nigro-striatal
pathway, and their degeneration leads to dopaminergic denervation of
the striatum and globus pallidus and, as a consequence, to bradyki-
nesia, rigidity, and resting tremors (Lees et al., 2009). PD is considered
as a mostly sporadic disease despite only a handful of environmental
causes have been identified. Among these, mitochondrial toxins, such
as MPTP and rotenone are able to lead to experimental parkinsonism
under defined experimental conditions (Bove et al., 2005). 10% of PD
are familial cases linked to mutations within PARK genes. A number of
these genes have been identified, and include α-Synuclein (PARK1),
Parkin (PARK2), PINK1 (PARK6) and DJ1 (PARK7) (Gupta et al., 2008).
Another disease affecting basal ganglia is Huntington's disease
(HD). HD is a monogenic neurodegenerative disease leading to dege-
neration of striatal neurons and clinically characterized by loss of
cognitive functions associated with major motor disturbance typified
by hyperkinesia (Berardelli et al., 1999). HD is caused by expansion in
the CAG repeats of the huntingtin gene, leading to expanded polyglu-
tamine tract in the huntingtin protein (Jou & Myers, 1995; Walker,
2007). The length of polyglutamine expansion is correlated with the
severity of the disease (Andrew et al., 1993; Rubinsztein et al., 1993).
5.2. Indirect evidence of dynein involvement in basal ganglia diseases
A number of indirect evidence suggest that dynein function might
be altered in PD and HD. First, axonal dystrophy, suggestive of axonal
transport impairment has been observed in PD brains (Lach et al.,
1992). Second, MPTP, a PD relevant injury, leads to defective axonal
transport, including increased dynein dependent transport (Morfini
et al., 2007), while axonal transport defects have been reported in
various animal or cellular models of HD (Gunawardena et al., 2003;
Szebenyi et al., 2003; Lee et al., 2004; Trushina et al., 2004; Sinadinos
et al., 2009).
Dynein is known to be involved in Golgi apparatus morphology,
and dynein disruption results in the fragmentation of this organelle.
Interestingly, PD brains as well as cellular and animal models also
display important fragmentation of the Golgi apparatus (Fujita et al.,
2006; Lin et al., 2009; Winslow et al., 2010) and the situation appears
similar in HD at least in cellular models (Caviston et al., 2007; Pardo
et al., 2010).
Dynein is crucially required for autophagy. Interestingly, both
mutant alpha-synuclein and mutant huntingtin are degraded by
autophagy in a dynein dependent manner (Ravikumar et al., 2005)
and the autophagic process itself appears largely abnormal in both HD
and PD (reviewed elsewhere (Banerjee et al., 2010; Wong & Cuervo,
2010)). For instance, it has been most recently shown using various
mouse and cellular models of HD that HD is associated with a primary
defect in cargo recognition of autophagic vacuoles (Martinez-Vicente
et al., 2010). In a similar manner, alpha-synuclein overexpression, a
situation occurring in some familial PD cases due to duplication of
alpha-synuclein gene locus (Ross et al., 2008b), inhibits macro-
autophagy (Winslow et al., 2010). Thus, both PD and HD appear to
involve abnormal autophagic response, which suggests potential
involvement of dynein.
5.3. Genetic evidence of dynein involvement in basal ganglia diseases
5.3.1. Dynein and dynactin mutations in basal ganglia diseases
Two lines of evidence show involvement of dynactin and dynein in
degeneration of basal ganglia. First, Farrer and collaborators described
five mutations in p150Glued linked to an atypical PD resistant to L-
DOPA, called Perry syndrome and characterized by early-onset
parkinsonism, depression, weight loss, hypoventilation, and TDP-43
proteinopathy (Farrer et al., 2009). Perry syndrome mutations are
distinct from the G59S mutation found in motor neuron diseases cases
(G71R, G71E, G71A, T72P and Q74P) but are nevertheless located in
the same protein domain (Farrer et al., 2009) (Fig. 5). Interestingly,
the biochemical properties of Perry syndrome associated mutant
P150Glued were similar to those of MND associated G59S mutant. The
functional consequences of Perry mutations on dynein function
remain however unknown. A more direct evidence of dynein
involvement in basal ganglia degeneration was recently provided by
our phenotypic analysis of mice with a point mutation in the dynein
heavy chain. Mice bearing the Cramping allele, previously thought to
develop motor neuron degeneration, displayed motor and behav-
ioural abnormalities including hindlimb clasping, early muscle
weakness, incoordination and hyperactivity reminiscent of mild HD
animal models. In addition to these phenotypic similarities, these
dynein mutant mice exhibit a striatal atrophy and ventricle
enlargement without associated degeneration of striatal neurons or
of substantia nigra dopaminergic neurons. In vitro, dynein mutant
striatal neurons displayed strongly impaired neuritic morphology
(Braunstein et al., 2010). Most interestingly, the analogy between
dynein mutant mice and HD animal models was also noted in the
periphery, with dynein mutant mice displaying increased adiposity
and compromised brown adipose tissue thermogenesis in a manner
similar to HD models (Weydt et al., 2006; Eschbach et al., 2011). Thus,
a point mutation in the dynein heavy chain is able to mimic, a mild
HD-like phenotype. To our knowledge, these data provide the first
direct proof that modifying dynein itself promotes a phenotype mild
but similar to HD.
5.3.2. Other dynein-related genes in basal ganglia diseases
Mutations in other genes linked to PD further indirectly support
the involvement of dynein in PD pathology. First, Saha et al. (2004)
had suggested that α-synuclein was associated with motor proteins
and vesicles. Alpha-synuclein mutations have been reported to
prevent the transport of the protein as well as its binding to brain
vesicles (Jensen et al., 1998; Saha et al., 2004). From a functional point
of view, alpha synuclein overexpression impairs microtubule depen-
dent trafficking (Lee et al., 2006) and leads to Golgi fragmentation
(Gosavi et al., 2002). More precisely, alpha-synuclein overexpression
is able to block ER-to Golgi trafficking in yeast and mammalian cells,
through inhibition of the small G-protein Rab1 and other ER/Golgi
SNARES (Cooper et al., 2006; Gitler et al., 2008; Thayanidhi et al.,
2010). The involvement of dynein in these functions of alpha-
synuclein has not been investigated up to now.
More direct evidence link recessive familial PD cases to dynein
dysfunction. Autophagy of mitochondria, a dynein dependent process,
appears as a genetic target in some familial PD cases. Mitochondria
that are unable to restore their membrane potential after a fission
event are committed to mitophagy (Twig et al., 2008; Wikstrom et al.,
2009). Interestingly, such dysfunctional mitochondria are bound by
parkin, a protein encoded by a gene mutant in PARK2 (Narendra et al.,
2008; Vives-Bauza et al., 2009). Parkin binding to impaired mito-
chondria is thought to mediate their transport to perinuclear areas
where these damaged organelles might be degraded through
autophagy (Narendra et al., 2008; Vives-Bauza et al., 2009).
Importantly, Parkin recruitment to dysfunctional mitochondria is
dependent upon stabilization of PINK1, mutant in PARK6, in
mitochondria (Matsuda et al., 2010; Narendra et al., 2010; Vives-
Bauza et al., 2010). Parkin-bound mitochondria are then docked to
dynein through the tubulin desacetylase called HDAC6 and this
docking triggers their transport to the aggresome through dynein
dependent transport (Hubbert et al., 2002; Kawaguchi et al., 2003;
Olzmann et al., 2007; Jiang et al., 2008). Interestingly, parkin and
HDAC6 are also involved in the transport of misfolded DJ-1, the
product of PARK7, to the aggresome (Olzmann et al., 2007). Thus,
 J. Eschbach, L. Dupuis / Pharmacology & Therapeutics 130 (2011) 348–363 355

dynein dependent transport of mitochondria and misfolded proteins
appears to be crucially involved in PD.
Besides PD, a number of evidence link dynein to huntingtin. First,
both huntingtin and its associated protein HAP-1 interact with
microtubules (DiFiglia et al., 1995), dynein (Caviston et al., 2007) and
p150Glued (Engelender et al., 1997; Gauthier et al., 2004). Huntingtin
appears to facilitate dynein mediated transport (Caviston et al., 2007)
but is also required for anterograde axonal transport (Gauthier et al.,
2004). Functionally, mutant huntingtin impairs retrograde axonal
transport (Szebenyi et al., 2003; Trushina et al., 2004) while wild type
overexpression increases retrograde axonal transport, presumably
dynein dependent (Her & Goldstein, 2008). Furthermore, mutant htt
striatal neurons exhibit dysmorphic dendrites (Laforet et al., 2001), in a
manner similar to that of dynein mutant striatal neurons. In all, available
evidence show that huntingtin and HAP-1 act as a docking platform to
modulate vesicular cargo attachment to molecular motors, including
dynein (Caviston et al., 2007) (Fig. 4).
Interestingly, HDAC6 has also been involved in the pathophysiology
of HD (Dompierre et al., 2007; Pandey et al., 2007) through its tubulin
deacetylation activity. Microtubule acetylation levels promote kinesin-1
binding and transport (Reed et al., 2006) and the recruitment of dynein
to microtubules (Dompierre et al., 2007). In HD brain, tubulin
acetylation is reduced which in turn, could be responsible for decrease
vesicular transport in HD brains (Fig. 4). This mechanism that directly
involves dynein, could be the key to explain the decrease of BDNF
transport in striatal neurons (Dompierre et al., 2007).
Thus, dynein involvement in PD and HD is indirectly suggested by
the occurrence of several mutations in modulators of some dynein-
dependent transport events, including dynactin, huntingtin, parkin,
PINK1, and potentially alpha-synuclein. In mice, a mutation in dynein
itself is able to lead to a disorder of basal ganglia, without associated
neurodegeneration. There are currently no known mutations in dynein
in such disorders.
5.4. Potential mechanisms underlying
dynein involvement in basal ganglia diseases
(Miller & Sheetz, 2004). Consistently, inhibition of complex I of the
electron transport chain with MPP + increased cytoplasmic dynein-
dependent retrograde fast axonal transport (FAT) and reduced
kinesin-1-mediated anterograde FAT through different mechanisms
that involve caspase 3 activation (Serulle et al., 2007) and protein
kinase C (Morfini et al., 2007).
In HD, recent work by Saudou, Humbert and colleagues showed
that a specific serine residue in huntingtin, S421, act as a molecular
switch between anterograde and retrograde transport (Colin et al.,
2008; Zala et al., 2008). This serine residue can be phosphorylated by
Akt and these authors had previously shown dysregulated Akt in HD
(Colin et al., 2005). Independently, Morfini, Brady and colleagues have
shown that mutant huntingtin impairs axonal transport through JNK
activation, and directly provided evidence of JNK mediated phosphor-
ylation of kinesin. Whether JNK phosphorylates dynein is currently
elusive and how this relates to other signalling pathways, including
Akt and huntingtin phosphorylation deserve further investigations.
5.5. Conclusion
In all, these observations point to dynein involvement to fin basal
ganglia neurodegeneration. Defects in axonal transport, Golgi ER
trafficking as well autophagy occurring in HD and PD indicate that
dynein could be a central point in the pathology, an hypothesis
strengthened by striatal atrophy in dynein mutant mice. However,
dynein mutant mice do not display any neuronal loss. Interestingly, a
large number of gene mutants in PD, as well as huntingtin, in basal
ganglia diseases, are known to modulate directly or indirectly at least
a subset of dynein functions. Nevertheless, dynein independent
effects of these proteins in these diseases also occur, as exemplified
by the transcriptional role of huntingtin (Zuccato et al., 2001; Cui et
al., 2006). Further studies with cell targeted loss of function of dynein
will be necessary to provide evidence of the direct involvement of
dynein in PD and HD.
6. Cytoplasmic dynein in Alzheimer's disease

Few studies investigated the causes of dynein dysfunction in PD 6.1. Alzheimer's disease
and HD. In PD, dynein dysfunction might be caused by mitochondrial
dysfunction. Indeed, mitochondrial toxins differentially modulate Alzheimer's disease (AD) is the most common form of dementia,
mitochondrial transport, in particular dynein mediated transport with about 25 million persons affected worldwide. Its prevalence is

Fig. 4. Dynein involvement in basal ganglia diseases. P150Glued, a component of the dynactin complex is mutated in Perry syndrome and the Cramping mutation in dynein heavy
chain leads to striatal atrophy in mouse. Alpha-synuclein, mutant in familial PD is a cargo of dynein and regulates ER-to-Golgi trafficking. Huntingtin (Htt) and its associated protein
HAP-1 are binding partners of dynein/dynactin. HDAC6, a direct dynein binding partner regulates mitophagy through its association with Parkin and PINK1, two gene mutants in PD
cases. When misfolded, DJ-1, also linked to PD, is transported to the aggresome through dynein dependent transport. Gene mutants in PD and HD are indicated by dark grey circles.
356 J. Eschbach, L. Dupuis / Pharmacology & Therapeutics 130 (2011) 348–363
estimated to be about 25 to 33% in people aged of more than 85 years.
From a clinical point of view, patients slowly lose episodic memory.
Disease progression includes aphasia, apraxia and agnosia and begins
with an early clinical stage called mild cognitive impairment (MCI).
AD is mostly a sporadic disease, with a few familial cases linked to
mutations in APP or in presenilins. Familial cases display earlier onset
and more severe disease course. Concerning sporadic cases, a major
risk factor is the apoE4 allele, which increases the risk of AD of three
times in heterozygotes and fifteen times in homozygotes. Pathology of
AD includes two typical lesions, amyloid plaques, that are extracel-
lular aggregates mainly composed of amyloid β peptides (Aβ), and
neurofibrillary tangles largely composed of intracellular hyperphos-
phorylated Tau aggregates. The clinics, genetics and mechanisms of
AD have been largely reviewed elsewhere (Blennow et al., 2006;
Bettens et al., 2010; Crews & Masliah, 2010).
6.2. Evidence for dynein involvement in AD
Evidence involving dynein in AD are largely indirect and dynein
might be involved in both amyloid plaques and neurofibrillary tangle
neurotoxicity. Indeed, as would be expected if AD is associated with
decreased dynein function, AD is associated with a number of axonal
defects and swellings, and these defects are present in human AD
brains, but also in animal models long before cognitive deficits are
obvious (Stokin et al., 2005; Stokin & Goldstein, 2006). However,
observations of axonal defects and swellings should not be taken as
proofs of axonal transport defects or of dynein involvement. In the
case of AD, such evidence are still lacking.
APP, the precursor of Aβ peptide, is transported by fast axonal
anterograde transport, is the subject to complex trafficking events
(Tang, 2009) and accumulates in pathological enlarged endosomes
(Cataldo et al., 2000; Kimura et al., 2009). A number of evidence
suggest that Aβ is transported to the synapse where it is secreted
(Sisodia et al., 1993; Lazarov et al., 2002, 2005) and a number of
laboratories have focused their efforts in determining whether the
amyloid cascade might be related with axonal transport impairment.
APP has been found to be interacting with kinesin-1 (Kamal et al.,
2000), but this has since been refuted (Lazarov et al., 2005). More
recently, Aβ peptide was shown to disrupt axonal transport in
cultured neurons (Rui et al., 2006; Pigino et al., 2009; Decker et al.,
2010). Whatever the underlying mechanism, most evidence linking
axonal transport machinery to amyloid plaques suggest an involve-
ment of rather anterograde transport than retrograde transport. For
instance, the reduction in kinesin gene dosage enhanced axonal
pathology in AD animal models (Stokin et al., 2005), while no similar
evidence have been published concerning dynein. The function of APP
itself in axonal transport is also unclear since APP deletions did not
modify axonal transport, while APP overexpression leads to axono-
pathy in an Aβ-independent manner (Stokin et al., 2008). The links
between APP and axonal transport in general, and dynein in
particular, thus remain largely unclear.
Recent studies showed that APP accumulates in enlarged endo-
somes during normal aging and AD. Endosomal pathology in AD is a
very early event that precedes Aβ deposition (Cataldo et al., 2000).
Interestingly, increasing endocytosis through Rab5 overexpression
largely mimics AD-related endosomal pathology, increases Aβ
deposition and promotes neuronal apoptosis (Grbovic et al., 2003;
Cataldo et al., 2004; Laifenfeld et al., 2007). Dynein function is
required for Rab5-mediated increase in endocytosis (Driskell et al.,
2007), suggesting that dynein function might increase Aβ deposition
through facilitation of Rab5 mediated endocytosis. However, knock-
ing down dynein in neurons mimicked aging-induced endosomal
pathology, led to accumulation of APP in endosomes and increased
beta-secretase cleavage of APP, leading to increased production of Aβ
(Kimura & Yanagisawa, 2007; Kimura et al., 2009). Thus, dynein might
be required for Aβ production, but its loss might also interfere with
endosomal trafficking of APP and accelerate amyloid plaque deposi-
tion. Further work is needed to resolve this discrepancy.
The second typical lesions of AD are neurofibrillary tangles (NFT),
mainly composed of accumulations of hyperphosphorylated tau.
Interestingly, Tau is a microtubule associated protein, that was
recently shown to differentially regulate kinesin and dynein motor
activity (Dixit et al., 2008). Tau is also a binding partner for dynactin,
and enhances dynactin binding to microtubules (Magnani et al.,
2007). Last, very recently, Tau reduction was shown to prevent Aβ
induced defect in axonal transport, both in anterograde and retro-
grade directions (Vossel et al., 2010). Thus, this crucial player in AD
pathogenesis appears also a potential modulator of dynein-dependent
transports.
6.3. Conclusions
Despite little doubt that axonal transport machinery and intracel-
lular trafficking events are involved in AD pathogenesis, the direct
evidence linking dynein to AD remain scarce, and the links provided
here between AD and dynein remain largely speculative. Further work
should be focused on more direct studies.
7. Cytoplasmic dynein in other neurodegenerative diseases
7.1. Prion diseases
Prion diseases are also known as transmissible spongiform en-
cephalopathies (TSEs). TSEs are uniformly lethal neurodegenerative
diseases, that are caused by an original infectious agent called prion.
Prions are abnormally folded isoforms of the cellular isoform of the
prion protein (PrPC). PrPC is necessary for prion diseases, and the
pathology requires the conversion of PrPC to the abnormal confor-
mation PrPSc. For review see Aguzzi and Heikenwalder (2006); Aguzzi
et al. (2008).
Dynein might be involved at different steps of prion mediated
neurodegeneration. First, dynein was thought to be key in prion
neuroinvasion. Prions are formed in the periphery and then “trans-
ported” in the CNS through unclear mechanisms in a process called
neuroinvasion. Several mechanisms might account for this phenom-
enon. First, PrPC might be converted to PrPSc locally, this conversion
then spreading from place to place (“Domino” theory). Alternatively,
PrPSc might be transported through microtubule dependent transport
(“Streetcar hypothesis”) (Aguzzi, 2003; Heikenwalder et al., 2007). In
the latter scenario, dynein could be the crucial motor for prion
transport. This hypothesis is substantiated by reports of PrPC transport
by fast axonal transport in both anterograde (Borchelt et al., 1994) and
retrograde directions (Moya et al., 2004) and by numerous evidence of
intracellular transport of both PrPC and PrPSc between the cell surface,
the ER, the Golgi and endosomes (Campana et al., 2005). However,
impairment of fast axonal transport through four-repeat tau over-
expression does not modify prion neuroinvasion (Kunzi et al., 2002)
and dynein mutant mice do not display delayed scrapie incubation
times (Hafezparast et al., 2005). These results suggest that a lack of
dynein involvement prion neuroinvasion, but do not provide strong
arguments for this.
Dynein dysfunction might also be the consequence of prion
mediated neurotoxicity. Indeed, the onset of prion disease in mice is
associated with important defects in retrograde axonal transport
(Ermolayev et al., 2009a, 2009b). From a mechanistic point of view,
this impairment in retrograde transport might be due to abnormal
localization of the small G-protein Rab7 which mediates dynein/
dynactin attachment to late endosomes (Ermolayev et al., 2009a)
(Fig. 5). In all, these results suggest that dynein dysfunction con-
tributes rather to the later events of prion diseases.
 J. Eschbach, L. Dupuis / Pharmacology & Therapeutics 130 (2011) 348–363
Fig. 5. Dynein involvement in peripheral neuropathies. Dynein cargoes, including NF‐L or mitochondrial mitofusin, are mutant in CMT families. Gigaxonin deletion impairs dynein
motor activity through increased expression of microtubule associated proteins MAP8 and MAP1C. Rab7 mutation in CMT constitutively activate Rab7 and alter dynein dépendant
endosomal trafficking. Genr mutants in peripheral neurophathie are indicated by dark grey circles.
7.2. Peripheral neuropathies
A vast array of NDDs are peripheral neuropathies, that affect either
sensory neurons or motor neurons or both. For instance, the most
common causes of peripheral neuropathies in western countries are
diabetes and alcoholism, while HIV and leprosy are the most common
infectious causes. These pathologies are extremely diverse, with
different etiologies (genetic, toxic, infectious…) and very diverse
clinical pictures and disease course. Peripheral neuropathies can thus
be acute or chronic, symmetrical or not, be axonal or involving
demyelination and involve only parts of the neuron or its whole. For
review see Fricker et al. (2008). A number of peripheral neuropathies
are inherited, and we would like here to focus on a few examples that
link these diseases to dynein function.
A number of inherited neuropathies are associated with docu-
mented defects in axonal transport (reviewed in (De Vos et al.,
2008)). In Charcot–Marie–Tooth disease (CMT) type 2E, caused by
mutations in the neurofilament light gene (NF-L), NF-L mutants
aggregates perturb the cytoskeletal network, in particular microtu-
bules, and disrupt the normal localization of mitochondria (Perez-Olle
et al., 2004). The overexpression of CMT2E-linked NF-L leads to
impaired axonal transport in vitro (Brownlees et al., 2002) and in vivo
(Dequen et al., 2010). Furthermore, in a mouse model of CMT2A
caused by mutations in mitofusin, axonal transport of mitochondria
was compromised (Baloh et al., 2007; Misko et al., 2010), and in giant
axonal neuropathy, caused by mutations in gigaxonin, deletion of
gigaxonin in mouse led to impaired retrograde axonal transport
(Allen et al., 2005; Ding et al., 2006). This impairment of axonal
transport appears not only true for axonal but also for demyelinating
hereditary neuropathies. Indeed, in an animal model of X-linked
demyelinating/type I Charcot–Marie–Tooth neuropathy (CMT1X), an
inherited peripheral neuropathy caused by mutations in the gap
junction protein connexin32, Vavlitou et al., 2010 observed reduced
axonal transport and axonal pathology before demyelination occurs.
Dynein dysfunction appears directly involved in at least a subset of
these diseases. First, the deletion in gigaxonin in mouse leads to
increased MAP8 and MAP1B LC levels. This, in turn, traps dynein and
impairs axonal retrograde transport (Allen et al., 2005; Ding et al.,
2006). More directly, mutations in the G-protein Rab7 trigger CMT2B
(Verhoeven et al., 2003) leading to constitutive activity of mutant
proteins (De Luca et al., 2008; Spinosa et al., 2008; McCray et al.,
2010). Rab7 controls dynein/dynactin recruitment to lysosomes and
late endosomes through its effector protein RILP (Jordens et al., 2001)
357
and was demonstrated to be essential for axonal retrograde transport
(Deinhardt et al., 2006). It is thus probable that CMT2B mutations
affect, in a still incompletely understood manner, dynein dependent
transport (Fig. 5).
7.3. Spinocerebellar ataxia
Spinocerebellar ataxias (SCAs) are a heterogenous group of genetic
disorders, characterized by progressive cerebellar ataxia leading to
postural abnormalities, and progressive motor incoordination. SCAs
are also associated with a number of other non-motor signs, including
cognitive deficits (Durr, 2010). There are currently 18 different SCA
loci, and most of these are associated with polyglutamine expansions.
Interestingly, ataxin 3, mutated in SCA3, is involved in aggresome
formation (Burnett & Pittman, 2005). Ataxin 3 possesses a deubiqui-
tinilating enzyme activity, is colocalized with HDAC6 and dynein and
appears indispensable for aggresome formation. The involvement of
dynein in SCA3 pathogenesis appears thus plausible (Fig. 6).
Mutations in β-III spectrin trigger another SCA, SCA5 (Ikeda et al.,
2006). β-III spectrin interacts with Arp1, a subunit of dynactin, and is
found in a complex with dynactin (Holleran et al., 2001). It is
noteworthy that β-III spectrin is required for dynein-mediated
translocation of late endosomes to microtubule minus ends and that
this requires the activities of Rab7-RILP and ORP1L (Johansson et al.,
2007). Thus β-III spectrin is hypothesized to facilitate protein
trafficking by linking dynein/dynactin to its cargoes. β-III spectrin
null mice display a SCA5-like phenotype, with Purkinje cell degen-
eration and progressive motor impairment, that could be due to loss
of neuronal and astrocytic transporter of glutamate, in particular of
EAAT4 (Perkins et al., 2010; Stankewich et al., 2010). Interestingly,
SCA5-associated mutations in β-III spectrin disrupt binding to Arp1,
and impair intracellular trafficking of EAAT4 (Clarkson et al., 2010).
Consistently, SCA5 mutations impair axonal transport in drosophila
(Lorenzo et al., 2010) and their toxicity is enhanced by dynein or
dynactin loss of functions. In all, it appears that SCA5 associated
mutations in β-III spectrin impair dynein function through defective
binding to dynactin, leading to abnormalities in glutamate transporter
intracellular trafficking and axonal transport impairment (Fig. 6).
8. Conclusions
Since the discovery of dynein, almost 25 years ago, research has
largely demonstrated that this molecular motor might play a key role
358 J. Eschbach, L. Dupuis / Pharmacology & Therapeutics 130 (2011) 348–363
Fig. 6. Dynein involvement in ataxias. β3-spectrin that is required for anchoring dynein/dynactin to vesicular cargoes is mutated in SCA5, while ataxin3, mutant in SCA3, is
colocalized with dynein and required for the formation of the aggresome. Gene mutants in SCAs are indicated by dark grey symbols.
in neurodegenerative diseases. Indeed, a number of cellular processes
that are almost entirely dynein-dependent are crucially involved in
NDDS, notably retrograde axonal transport, endosomal and lysosomal
trafficking and protein degradation. Moreover, a number of dynein
interactors or regulators are mutant in various neurodegenerative
diseases, clearly showing that the motor activity of dynein is certainly
critical for neuronal survival.
Despite this wealth of knowledge, it has to be pointed out that to
date, most of the available evidence of involvement of dynein itself is
indirect, and mostly based on dynamitin overexpression or on over-
expression of mutant P150Glued or other mutant interactors of dynein.
In this context, a number of these proteins have been recently shown
to possess dynein independent function. This includes notably dynac-
tin and bicaudal D which regulate not only the function of dynein but
also that of kinesins (Berezuk & Schroer, 2007; Splinter et al., 2010).
Similarly, huntingtin appears to modulate not only dynein but also
kinesin and is documented to have transcriptional effects on BDNF
expression and PGC1α co-activator function (Zuccato et al., 2001; Cui
et al., 2006). Moreover, besides a regulation of intracellular transport,
p150Glued protein has been shown to act as a docking protein and has
been recently suggested to affect gene transcription through direct
modulation of transcription factors (Lee et al., 2009; Shrum et al.,
2009). Thus direct proofs of involvement of dynein motor itself in
NDDs are largely lacking. This lack of evidence might well be due to
the obligate need of dynein for embryonic development.
Last, it remains unknown whether the motor activity of dynein is
rate-limiting in neuronal survival or whether it is rather the quality of
the material transported that bears any importance. In this respect, it
is striking to note that dynein heterozygous mice appeared grossly
normal while a point mutation on a single dynein heavy chain allele is
sufficient to lead to a number of neurologic and peripheral pheno-
types (Harada et al., 1998; Hafezparast et al., 2003; Dupuis et al., 2009;
Braunstein et al., 2010) suggesting that the mutant allele possess a
toxic gain of function over at least one crucial function for dynein in
neuronal physiology. Here again, genetic deletion of dynein in
neurons of interest might show the dose dependency of neuronal
survival to dynein motor activity.
Acknowledgments
Work in our laboratory is supported by grants from Fondation
pour la Recherche Médicale, Association pour la Recherche sur la
Sclérose Latérale Amyotrophique (ARSla), Amyotrophic Lateral
Sclerosis Association (grant 1698), Fondation Thierry Latran, Associ-
ation française de lutte contre les myopathies (AFM) and association
pour la recherche et le developpement de moyens de lutte contre les
maladies neurodégénératives (AREMANE).
References
Aguzzi, A. (2003). Prions and the immune system: a journey through gut, spleen, and
nerves. Adv Immunol 81, 123−171.
Aguzzi, A., & Heikenwalder, M. (2006). Pathogenesis of prion diseases: current status
and future outlook. Nat Rev Microbiol 4, 765−775.
Aguzzi, A., Sigurdson, C., & Heikenwaelder, M. (2008). Molecular mechanisms of prion
pathogenesis. Annu Rev Pathol 3, 11−40.
Ahmad-Annuar, A., Shah, P., Hafezparast, M., Hummerich, H., Witherden, A. S.,
Morrison, K. E., et al. (2003). No association with common Caucasian genotypes
in exons 8, 13 and 14 of the human cytoplasmic dynein heavy chain gene
(DNCHC1) and familial motor neuron disorders. Amyotroph Lateral Scler Other Mot
Neuron Disord 4, 150−157.
Alexander, G. E., Crutcher, M. D., & DeLong, M. R. (1990). Basal ganglia-thalamocortical
circuits: parallel substrates for motor, oculomotor, “prefrontal” and “limbic”
functions. Prog Brain Res 85, 119−146.
Allan, V. (1995). Protein phosphatase 1 regulates the cytoplasmic dynein-driven
formation of endoplasmic reticulum networks in vitro. J Cell Biol 128, 879−891.
Allen, E., Ding, J., Wang, W., Pramanik, S., Chou, J., Yau, V., et al. (2005). Gigaxonin-
controlled degradation of MAP1B light chain is critical to neuronal survival. Nature
438, 224−228.
Andersson, L., Bostrom, P., Ericson, J., Rutberg, M., Magnusson, B., Marchesan, D., et al.
(2006). PLD1 and ERK2 regulate cytosolic lipid droplet formation. J Cell Sci 119,
2246−2257.
Andrew, S. E., Goldberg, Y. P., Kremer, B., Telenius, H., Theilmann, J., Adam, S., et al.
(1993). The relationship between trinucleotide (CAG) repeat length and clinical
features of Huntington's disease. Nat Genet 4, 398−403.
Aniento, F., Emans, N., Griffiths, G., & Gruenberg, J. (1993). Cytoplasmic dynein-
dependent vesicular transport from early to late endosomes. J Cell Biol 123,
1373−1387.
Baloh, R. H., Schmidt, R. E., Pestronk, A., & Milbrandt, J. (2007). Altered axonal
mitochondrial transport in the pathogenesis of Charcot–Marie–Tooth disease from
mitofusin 2 mutations. J Neurosci 27, 422−430.
Banerjee, R., Beal, M. F., & Thomas, B. (2010). Autophagy in neurodegenerative
disorders: pathogenic roles and therapeutic implications. Trends Neurosci 33(12),
541−549.
Berardelli, A., Noth, J., Thompson, P. D., Bollen, E. L., Curra, A., Deuschl, G., et al. (1999).
Pathophysiology of chorea and bradykinesia in Huntington's disease. Mov Disord
14, 398−403.
Berezuk, M. A., & Schroer, T. A. (2007). Dynactin enhances the processivity of kinesin-2.
Traffic 8, 124−129.
Bettens, K., Sleegers, K., & Van Broeckhoven, C. (2010). Current status on Alzheimer
disease molecular genetics: from past, to present, to future. Hum Mol Genet 19,
R4−R11.
Binet, S., & Meininger, V. (1988). Modifications of microtubule proteins in ALS nerve
precede detectable histologic and ultrastructural changes. Neurology 38,
1596−1600.
Blennow, K., de Leon, M. J., & Zetterberg, H. (2006). Alzheimer's disease. Lancet 368,
387−403.
Boillee, S., Vande Velde, C., & Cleveland, D. W. (2006). ALS: a disease of motor neurons
and their nonneuronal neighbors. Neuron 52, 39−59.
Borchelt, D. R., Koliatsos, V. E., Guarnieri, M., Pardo, C. A., Sisodia, S. S., & Price, D. L.
(1994). Rapid anterograde axonal transport of the cellular prion glycoprotein in the
peripheral and central nervous systems. J Biol Chem 269, 14711−14714.
 J. Eschbach, L. Dupuis / Pharmacology & Therapeutics 130 (2011) 348–363
Bostrom, P., Andersson, L., Rutberg, M., Perman, J., Lidberg, U., Johansson, B. R., et al.
(2007). SNARE proteins mediate fusion between cytosolic lipid droplets and are
implicated in insulin sensitivity. Nat Cell Biol 9, 1286−1293.
Bostrom, P., Rutberg, M., Ericsson, J., Holmdahl, P., Andersson, L., Frohman, M. A., et al.
(2005). Cytosolic lipid droplets increase in size by microtubule-dependent complex
formation. Arterioscler Thromb Vasc Biol 25, 1945−1951.
Bove, J., Prou, D., Perier, C., & Przedborski, S. (2005). Toxin-induced models of
Parkinson's disease. NeuroRx 2, 484−494.
Braunstein, K. E., Eschbach, J., Rona-Voros, K., Soylu, R., Mikrouli, E., Larmet, Y., et al.
(2010). A point mutation in the dynein heavy chain gene leads to striatal atrophy
and compromises neurite outgrowth of striatal neurons. Hum Mol Genet. doi:
10.1093/hmg/ddq1361.
Breuer, A. C., Lynn, M. P., Atkinson, M. B., Chou, S. M., Wilbourn, A. J., Marks, K. E., et al.
(1987). Fast axonal transport in amyotrophic lateral sclerosis: an intra-axonal
organelle traffic analysis. Neurology 37, 738−748.
Brooks, B. R., Sanjak, M., Belden, D., Juhasz-Poscine, K., & Waclawik, A. (2000). Natural
history of amyotrophic lateral sclerosis. In R. H. J. Brown, V. Meininger, & M. Swash
(Eds.), Amyotrophic Lateral Sclerosis (pp. 31−58). London: Dunitz.
Brownlees, J., Ackerley, S., Grierson, A. J., Jacobsen, N. J., Shea, K., Anderton, B. H., et al.
(2002). Charcot–Marie–Tooth disease neurofilament mutations disrupt neurofila-
ment assembly and axonal transport. Hum Mol Genet 11, 2837−2844.
Burkhardt, J. K., Echeverri, C. J., Nilsson, T., & Vallee, R. B. (1997). Overexpression
of the dynamitin (p50) subunit of the dynactin complex disrupts dynein-
dependent maintenance of membrane organelle distribution. J Cell Biol 139,
469−484.
Burnett, B. G., & Pittman, R. N. (2005). The polyglutamine neurodegenerative protein
ataxin 3 regulates aggresome formation. Proc Natl Acad Sci U S A 102, 4330−4335.
Campana, V., Sarnataro, D., & Zurzolo, C. (2005). The highways and byways of prion
protein trafficking. Trends Cell Biol 15, 102−111.
Cataldo, A. M., Petanceska, S., Terio, N. B., Peterhoff, C. M., Durham, R., Mercken, M., et al.
(2004). Abeta localization in abnormal endosomes: association with earliest Abeta
elevations in AD and Down syndrome. Neurobiol Aging 25, 1263−1272.
Cataldo, A. M., Peterhoff, C. M., Troncoso, J. C., Gomez-Isla, T., Hyman, B. T., & Nixon, R. A.
(2000). Endocytic pathway abnormalities precede amyloid beta deposition in
sporadic Alzheimer's disease and Down syndrome: differential effects of APOE
genotype and presenilin mutations. Am J Pathol 157, 277−286.
Caviston, J. P., Ross, J. L., Antony, S. M., Tokito, M., & Holzbaur, E. L. (2007). Huntingtin
facilitates dynein/dynactin-mediated vesicle transport. Proc Natl Acad Sci U S A 104,
10045−10050.
Chen, H. J., Anagnostou, G., Chai, A., Withers, J., Morris, A., Adhikaree, J., et al. (2010).
Characterisation of the properties of a novel mutation in VAPB in familial ALS. J Biol
Chem 285(51), 40266−40281.
Chen, X. J., Levedakou, E. N., Millen, K. J., Wollmann, R. L., Soliven, B., & Popko, B. (2007).
Proprioceptive sensory neuropathy in mice with a mutation in the cytoplasmic
Dynein heavy chain 1 gene. J Neurosci 27, 14515−14524.
Chevalier-Larsen, E., & Holzbaur, E. L. (2006). Axonal transport and neurodegenerative
disease. Biochim Biophys Acta 1762, 1094−1108.
Chevalier-Larsen, E. S., Wallace, K. E., Pennise, C. R., & Holzbaur, E. L. (2008). Lysosomal
proliferation and distal degeneration in motor neurons expressing the G59S
mutation in the p150Glued subunit of dynactin. Hum Mol Genet 17, 1946−1955.
Chow, C. Y., Landers, J. E., Bergren, S. K., Sapp, P. C., Grant, A. E., Jones, J. M., et al. (2009).
Deleterious variants of FIG4, a phosphoinositide phosphatase, in patients with ALS.
Am J Hum Genet 84, 85−88.
Clarkson, Y. L., Gillespie, T., Perkins, E. M., Lyndon, A. R., & Jackson, M. (2010). Beta-III
spectrin mutation L253P associated with spinocerebellar ataxia type 5 interferes
with binding to Arp1 and protein trafficking from the Golgi. Hum Mol Genet 19,
3634−3641.
Colin, E., Regulier, E., Perrin, V., Durr, A., Brice, A., Aebischer, P., et al. (2005). Akt is
altered in an animal model of Huntington's disease and in patients. Eur J Neurosci
21, 1478−1488.
Colin, E., Zala, D., Liot, G., Rangone, H., Borrell-Pages, M., Li, X. J., et al. (2008). Huntingtin
phosphorylation acts as a molecular switch for anterograde/retrograde transport in
neurons. EMBO J 27, 2124−2134.
Cooper, A. A., Gitler, A. D., Cashikar, A., Haynes, C. M., Hill, K. J., Bhullar, B., et al. (2006).
Alpha-synuclein blocks ER-Golgi traffic and Rab1 rescues neuron loss in Parkinson's
models. Science 313, 324−328.
Corthesy-Theulaz, I., Pauloin, A., & Pfeffer, S. R. (1992). Cytoplasmic dynein participates
in the centrosomal localization of the Golgi complex. J Cell Biol 118, 1333−1345.
Cosker, K. E., Courchesne, S. L., & Segal, R. A. (2008). Action in the axon: generation and
transport of signaling endosomes. Curr Opin Neurobiol 18, 270−275.
Cox, L. E., Ferraiuolo, L., Goodall, E. F., Heath, P. R., Higginbottom, A., Mortiboys, H., et al.
(2010). Mutations in CHMP2B in lower motor neuron predominant amyotrophic
lateral sclerosis (ALS). PLoS ONE 5, e9872.
Creppe, C., Malinouskaya, L., Volvert, M. L., Gillard, M., Close, P., Malaise, O., et al. (2009).
Elongator controls the migration and differentiation of cortical neurons through
acetylation of alpha-tubulin. Cell 136, 551−564.
Crews, L., & Masliah, E. (2010). Molecular mechanisms of neurodegeneration in
Alzheimer's disease. Hum Mol Genet 19, R12−R20.
Cuervo, A. M., Wong, E. S., & Martinez-Vicente, M. (2010). Protein degradation,
aggregation, and misfolding. Mov Disord 25(Suppl. 1), S49−S54.
Cui, L., Jeong, H., Borovecki, F., Parkhurst, C. N., Tanese, N., & Krainc, D. (2006).
Transcriptional repression of PGC-1alpha by mutant huntingtin leads to mito-
chondrial dysfunction and neurodegeneration. Cell 127, 59−69.
Dagoneau, N., Goulet, M., Genevieve, D., Sznajer, Y., Martinovic, J., Smithson, S., et al.
(2009). DYNC2H1 mutations cause asphyxiating thoracic dystrophy and short rib-
polydactyly syndrome, type III. Am J Hum Genet 84, 706−711.
359
De Luca, A., Progida, C., Spinosa, M. R., Alifano, P., & Bucci, C. (2008). Characterization of
the Rab7K157N mutant protein associated with Charcot–Marie–Tooth type 2B.
Biochem Biophys Res Commun 372, 283−287.
De Vos, K. J., Chapman, A. L., Tennant, M. E., Manser, C., Tudor, E. L., Lau, K. F., et al. (2007).
Familial amyotrophic lateral sclerosis-linked SOD1 mutants perturb fast axonal
transport to reduce axonal mitochondria content. Hum Mol Genet 16, 2720−2728.
De Vos, K. J., Grierson, A. J., Ackerley, S., & Miller, C. C. (2008). Role of axonal transport in
neurodegenerative diseases. Annu Rev Neurosci 31, 151−173.
Decker, H., Lo, K. Y., Unger, S. M., Ferreira, S. T., & Silverman, M. A. (2010). Amyloid-beta
peptide oligomers disrupt axonal transport through an NMDA receptor-dependent
mechanism that is mediated by glycogen synthase kinase 3beta in primary cultured
hippocampal neurons. J Neurosci 30, 9166−9171.
Deinhardt, K., Salinas, S., Verastegui, C., Watson, R., Worth, D., Hanrahan, S., et al.
(2006). Rab5 and Rab7 control endocytic sorting along the axonal retrograde
transport pathway. Neuron 52, 293−305.
Delcroix, J. D., Valletta, J. S., Wu, C., Hunt, S. J., Kowal, A. S., & Mobley, W. C. (2003). NGF
signaling in sensory neurons: evidence that early endosomes carry NGF retrograde
signals. Neuron 39, 69−84.
Deng, H. X., Zhai, H., Bigio, E. H., Yan, J., Fecto, F., Ajroud, K., et al. (2010). FUS-
immunoreactive inclusions are a common feature in sporadic and non-SOD1
familial amyotrophic lateral sclerosis. Ann Neurol 67, 739−748.
Dequen, F., Filali, M., Lariviere, R. C., Perrot, R., Hisanaga, S., & Julien, J. P. (2010).
Reversal of neuropathy phenotypes in conditional mouse model of Charcot–Marie–
Tooth disease type 2E. Hum Mol Genet 19, 2616−2629.
Devon, R. S., Orban, P. C., Gerrow, K., Barbieri, M. A., Schwab, C., Cao, L. P., et al. (2006).
Als2-deficient mice exhibit disturbances in endosome trafficking associated with
motor behavioral abnormalities. Proc Natl Acad Sci U S A 103, 9595−9600.
Dienstbier, M., & Li, X. (2009). Bicaudal-D and its role in cargo sorting by microtubule-
based motors. Biochem Soc Trans 37, 1066−1071.
DiFiglia, M., Sapp, E., Chase, K., Schwarz, C., Meloni, A., Young, C., et al. (1995).
Huntingtin is a cytoplasmic protein associated with vesicles in human and rat brain
neurons. Neuron 14, 1075−1081.
Ding, J., Allen, E., Wang, W., Valle, A., Wu, C., Nardine, T., et al. (2006). Gene targeting of
GAN in mouse causes a toxic accumulation of microtubule-associated protein 8 and
impaired retrograde axonal transport. Hum Mol Genet 15, 1451−1463.
Dixit, R., Ross, J. L., Goldman, Y. E., & Holzbaur, E. L. (2008). Differential regulation of
dynein and kinesin motor proteins by tau. Science 319, 1086−1089.
Dompierre, J. P., Godin, J. D., Charrin, B. C., Cordelieres, F. P., King, S. J., Humbert, S., et al.
(2007). Histone deacetylase 6 inhibition compensates for the transport deficit in
Huntington's disease by increasing tubulin acetylation. J Neurosci 27, 3571−3583.
Driskell, O. J., Mironov, A., Allan, V. J., & Woodman, P. G. (2007). Dynein is required for
receptor sorting and the morphogenesis of early endosomes. Nat Cell Biol 9,
113−120.
Dupuis, L., & Echaniz-Laguna, A. (2010). Skeletal muscle in motor neuron diseases:
therapeutic target and delivery route for potential treatments. Curr Drug Targets 11
(10), 1250−1261.
Dupuis, L., Fergani, A., Braunstein, K. E., Eschbach, J., Holl, N., Rene, F., et al. (2009). Mice
with a mutation in the dynein heavy chain 1 gene display sensory neuropathy but
lack motor neuron disease. Exp Neurol 215, 146−152.
Dupuis, L., & Loeffler, J. P. (2009). Neuromuscular junction destruction during
amyotrophic lateral sclerosis: insights from transgenic models. Curr Opin
Pharmacol 9, 341−346.
Durr, A. (2010). Autosomal dominant cerebellar ataxias: polyglutamine expansions and
beyond. Lancet Neurol 9, 885−894.
El-Kadi, A. M., Bros-Facer, V., Deng, W., Philpott, A., Stoddart, E., Banks, G., et al. (2010). The
legs at odd angles (Loa) mutation in cytoplasmic dynein ameliorates mitochondrial
function in SOD1G93A mouse model for motor neuron disease. J Biol Chem 285,
18627−18639.
Engelender, S., Sharp, A. H., Colomer, V., Tokito, M. K., Lanahan, A., Worley, P., et al.
(1997). Huntingtin-associated protein 1 (HAP1) interacts with the p150Glued
subunit of dynactin. Hum Mol Genet 6, 2205−2212.
Ermolayev, V., Cathomen, T., Merk, J., Friedrich, M., Hartig, W., Harms, G. S., et al.
(2009a). Impaired axonal transport in motor neurons correlates with clinical prion
disease. PLoS Pathog 5, e1000558.
Ermolayev, V., Friedrich, M., Nozadze, R., Cathomen, T., Klein, M. A., Harms, G. S., et al.
(2009b). Ultramicroscopy reveals axonal transport impairments in cortical motor
neurons at prion disease. Biophys J 96, 3390−3398.
Eschbach, J., Fergani, A., Oudart, H., Robin, J. P., Rene, F., de Aguilar, J. L., et al. (2011).
Mutations in cytoplasmic dynein lead to a Huntington's disease-like defect in energy
metabolism of brown and white adipose tissues. Biochim Biophys Acta 1812(1), 59−69.
Eymard-Pierre, E., Lesca, G., Dollet, S., Santorelli, F. M., di Capua, M., Bertini, E., et al.
(2002). Infantile-onset ascending hereditary spastic paralysis is associated with
mutations in the alsin gene. Am J Hum Genet 71, 518−527.
Farrer, M. J., Hulihan, M. M., Kachergus, J. M., Dachsel, J. C., Stoessl, A. J., Grantier, L. L.,
et al. (2009). DCTN1 mutations in Perry syndrome. Nat Genet 41, 163−165.
Filimonenko, M., Stuffers, S., Raiborg, C., Yamamoto, A., Malerod, L., Fisher, E. M., et al.
(2007). Functional multivesicular bodies are required for autophagic clearance of
protein aggregates associated with neurodegenerative disease. J Cell Biol 179,
485−500.
Frederick, R. L., & Shaw, J. M. (2007). Moving mitochondria: establishing distribution of
an essential organelle. Traffic 8, 1668−1675.
Fricker, B., Muller, A., & Rene, F. (2008). Evaluation tools and animal models of
peripheral neuropathies. Neurodegener Dis 5, 72−108.
Fridolfsson, H. N., Ly, N., Meyerzon, M., & Starr, D. A. (2010). UNC-83 coordinates
kinesin-1 and dynein activities at the nuclear envelope during nuclear migration.
Dev Biol 338, 237−250.
360 J. Eschbach, L. Dupuis / Pharmacology & Therapeutics 130 (2011) 348–363
Fujita, Y., Ohama, E., Takatama, M., Al-Sarraj, S., & Okamoto, K. (2006). Fragmentation of
Golgi apparatus of nigral neurons with alpha-synuclein-positive inclusions in
patients with Parkinson's disease. Acta Neuropathol 112, 261−265.
Funke, A. D., Esser, M., Kruttgen, A., Weis, J., Mitne-Neto, M., Lazar, M., et al. (2010). The
p.P56S mutation in the VAPB gene is not due to a single founder: the first European
case. Clin Genet 77, 302−303.
Gauthier, L. R., Charrin, B. C., Borrell-Pages, M., Dompierre, J. P., Rangone, H., Cordelieres,
F. P., et al. (2004). Huntingtin controls neurotrophic support and survival of neurons
by enhancing BDNF vesicular transport along microtubules. Cell 118, 127−138.
Gee, M. A., Heuser, J. E., & Vallee, R. B. (1997). An extended microtubule-binding
structure within the dynein motor domain. Nature 390, 636−639.
Gitler, A. D., Bevis, B. J., Shorter, J., Strathearn, K. E., Hamamichi, S., Su, L. J., et al. (2008).
The Parkinson's disease protein alpha-synuclein disrupts cellular Rab homeostasis.
Proc Natl Acad Sci U S A 105, 145−150.
Godin, J. D., Colombo, K., Molina-Calavita, M., Keryer, G., Zala, D., Charrin, B. C., et al.
(2010). Huntingtin is required for mitotic spindle orientation and mammalian
neurogenesis. Neuron 67, 392−406.
Gonatas, N. K., Stieber, A., & Gonatas, J. O. (2006). Fragmentation of the Golgi apparatus
in neurodegenerative diseases and cell death. J Neurol Sci 246, 21−30.
Gonzalez de Aguilar, J. L., Echaniz-Laguna, A., Fergani, A., Rene, F., Meininger, V., Loeffler, J. P.,
et al. (2007). Amyotrophic lateral sclerosis: all roads lead to Rome. J Neurochem 101(5),
1153−1160.
Gosavi, N., Lee, H. J., Lee, J. S., Patel, S., & Lee, S. J. (2002). Golgi fragmentation occurs in
the cells with prefibrillar alpha-synuclein aggregates and precedes the formation of
fibrillar inclusion. J Biol Chem 277, 48984−48992.
Grbovic, O. M., Mathews, P. M., Jiang, Y., Schmidt, S. D., Dinakar, R., Summers-Terio, N. B.,
et al. (2003). Rab5-stimulated up-regulation of the endocytic pathway increases
intracellular beta-cleaved amyloid precursor protein carboxyl-terminal fragment
levels and Abeta production. J Biol Chem 278, 31261−31268.
Greenway, M. J., Andersen, P. M., Russ, C., Ennis, S., Cashman, S., Donaghy, C., et al.
(2006). ANG mutations segregate with familial and ‘sporadic’ amyotrophic lateral
sclerosis. Nat Genet 38, 411−413.
Gross, S. P., Welte, M. A., Block, S. M., & Wieschaus, E. F. (2000). Dynein-mediated cargo
transport in vivo. A switch controls travel distance. J Cell Biol 148, 945−956.
Gunawardena, S., Her, L. S., Brusch, R. G., Laymon, R. A., Niesman, I. R., Gordesky-Gold, B.,
et al. (2003). Disruption of axonal transport by loss of huntingtin or expression of
pathogenic polyQ proteins in Drosophila. Neuron 40, 25−40.
Gupta, A., Dawson, V. L., & Dawson, T. M. (2008). What causes cell death in Parkinson's
disease? Ann Neurol 64(Suppl. 2), S3−S15.
Hadano, S., Benn, S. C., Kakuta, S., Otomo, A., Sudo, K., Kunita, R., et al. (2006). Mice
deficient in the Rab5 guanine nucleotide exchange factor ALS2/alsin exhibit age-
dependent neurological deficits and altered endosome trafficking. Hum Mol Genet
15, 233−250.
Hadano, S., Hand, C. K., Osuga, H., Yanagisawa, Y., Otomo, A., Devon, R. S., et al. (2001). A
gene encoding a putative GTPase regulator is mutated in familial amyotrophic
lateral sclerosis 2. Nat Genet 29, 166−173.
Hafezparast, M., Brandner, S., Linehan, J., Martin, J. E., Collinge, J., & Fisher, E. M. (2005).
Prion disease incubation time is not affected in mice heterozygous for a dynein
mutation. Biochem Biophys Res Commun 326, 18−22.
Hafezparast, M., Klocke, R., Ruhrberg, C., Marquardt, A., Ahmad-Annuar, A., Bowen, S.,
et al. (2003). Mutations in dynein link motor neuron degeneration to defects in
retrograde transport. Science 300, 808−812.
Harada, A., Takei, Y., Kanai, Y., Tanaka, Y., Nonaka, S., & Hirokawa, N. (1998). Golgi
vesiculation and lysosome dispersion in cells lacking cytoplasmic dynein. J Cell Biol
141, 51−59.
Heerssen, H. M., Pazyra, M. F., & Segal, R. A. (2004). Dynein motors transport activated
Trks to promote survival of target-dependent neurons. Nat Neurosci 7, 596−604.
Heikenwalder, M., Julius, C., & Aguzzi, A. (2007). Prions and peripheral nerves: a deadly
rendezvous. J Neurosci Res 85, 2714−2725.
Her, L. S., & Goldstein, L. S. (2008). Enhanced sensitivity of striatal neurons to axonal
transport defects induced by mutant huntingtin. J Neurosci 28, 13662−13672.
Hirokawa, N. (1998). Kinesin and dynein superfamily proteins and the mechanism of
organelle transport. Science 279, 519−526.
Hirokawa, N., Niwa, S., & Tanaka, Y. (2010). Molecular motors in neurons: transport
mechanisms and roles in brain function, development, and disease. Neuron 68,
610−638.
Hollenbeck, P. J., & Saxton, W. M. (2005). The axonal transport of mitochondria. J Cell Sci
118, 5411−5419.
Holleran, E. A., Ligon, L. A., Tokito, M., Stankewich, M. C., Morrow, J. S., & Holzbaur, E. L.
(2001). Beta III spectrin binds to the Arp1 subunit of dynactin. J Biol Chem 276,
36598−36605.
Holzbaur, E. L., & Vallee, R. B. (1994). DYNEINS: molecular structure and cellular
function. Annu Rev Cell Biol 10, 339−372.
Hoogenraad, C. C., Akhmanova, A., Howell, S. A., Dortland, B. R., De Zeeuw, C. I.,
Willemsen, R., et al. (2001). Mammalian Golgi-associated Bicaudal-D2 functions in
the dynein–dynactin pathway by interacting with these complexes. EMBO J 20,
4041−4054.
Hubbert, C., Guardiola, A., Shao, R., Kawaguchi, Y., Ito, A., Nixon, A., et al. (2002). HDAC6
is a microtubule-associated deacetylase. Nature 417, 455−458.
Hurley, J. H. (2008). ESCRT complexes and the biogenesis of multivesicular bodies. Curr
Opin Cell Biol 20, 4−11.
Ikeda, Y., Dick, K. A., Weatherspoon, M. R., Gincel, D., Armbrust, K. R., Dalton, J. C., et al.
(2006). Spectrin mutations cause spinocerebellar ataxia type 5. Nat Genet 38,
184−190.
Ilieva, H., Polymenidou, M., & Cleveland, D. W. (2009). Non-cell autonomous toxicity in
neurodegenerative disorders: ALS and beyond. J Cell Biol 187, 761−772.
Ilieva, H. S., Yamanaka, K., Malkmus, S., Kakinohana, O., Yaksh, T., Marsala, M., et al.
(2008). Mutant dynein (Loa) triggers proprioceptive axon loss that extends
survival only in the SOD1 ALS model with highest motor neuron death. Proc Natl
Acad Sci U S A 105, 12599−12604.
Jahreiss, L., Menzies, F. M., & Rubinsztein, D. C. (2008). The itinerary of autophago-
somes: from peripheral formation to kiss-and-run fusion with lysosomes. Traffic 9,
574−587.
Jensen, P. H., Nielsen, M. S., Jakes, R., Dotti, C. G., & Goedert, M. (1998). Binding of
alpha-synuclein to brain vesicles is abolished by familial Parkinson's disease
mutation. J Biol Chem 273, 26292−26294.
Jiang, Q., Ren, Y., & Feng, J. (2008). Direct binding with histone deacetylase 6 mediates the
reversible recruitment of parkin to the centrosome. J Neurosci 28, 12993−13002.
Johansson, M., Rocha, N., Zwart, W., Jordens, I., Janssen, L., Kuijl, C., et al. (2007).
Activation of endosomal dynein motors by stepwise assembly of Rab7-RILP-
p150Glued, ORP1L, and the receptor betalll spectrin. J Cell Biol 176, 459−471.
Jordens, I., Fernandez-Borja, M., Marsman, M., Dusseljee, S., Janssen, L., Calafat, J., et al.
(2001). The Rab7 effector protein RILP controls lysosomal transport by inducing the
recruitment of dynein–dynactin motors. Curr Biol 11, 1680−1685.
Jou, Y. S., & Myers, R. M. (1995). Evidence from antibody studies that the CAG repeat in the
Huntington disease gene is expressed in the protein. Hum Mol Genet 4, 465−469.
Kabashi, E., Valdmanis, P. N., Dion, P., Spiegelman, D., McConkey, B. J., Vande Velde, C.,
et al. (2008). TARDBP mutations in individuals with sporadic and familial
amyotrophic lateral sclerosis. Nat Genet 40, 572−574.
Kamal, A., Stokin, G. B., Yang, Z., Xia, C. H., & Goldstein, L. S. (2000). Axonal transport of
amyloid precursor protein is mediated by direct binding to the kinesin light chain
subunit of kinesin-I. Neuron 28, 449−459.
Kardon, J. R., & Vale, R. D. (2009). Regulators of the cytoplasmic dynein motor. Nat Rev
Mol Cell Biol 10, 854−865.
Karki, S., & Holzbaur, E. L. (1995). Affinity chromatography demonstrates a direct
binding between cytoplasmic dynein and the dynactin complex. J Biol Chem 270,
28806−28811.
Katsuno, M., Adachi, H., Minamiyama, M., Waza, M., Tokui, K., Banno, H., et al. (2006).
Reversible disruption of dynactin 1-mediated retrograde axonal transport in
polyglutamine-induced motor neuron degeneration. J Neurosci 26, 12106−12117.
Kawaguchi, Y., Kovacs, J. J., McLaurin, A., Vance, J. M., Ito, A., & Yao, T. P. (2003). The
deacetylase HDAC6 regulates aggresome formation and cell viability in response to
misfolded protein stress. Cell 115, 727−738.
Kimura, N., Inoue, M., Okabayashi, S., Ono, F., & Negishi, T. (2009). Dynein dysfunction
induces endocytic pathology accompanied by an increase in Rab GTPases: a
potential mechanism underlying age-dependent endocytic dysfunction. J Biol Chem
284, 31291−31302.
Kimura, N., & Yanagisawa, K. (2007). Endosomal accumulation of GM1 ganglioside-
bound amyloid beta-protein in neurons of aged monkey brains. Neuroreport 18,
1669−1673.
King, S. J., & Schroer, T. A. (2000). Dynactin increases the processivity of the cytoplasmic
dynein motor. Nat Cell Biol 2, 20−24.
King, S. M., Barbarese, E., Dillman, J. F., 3rd, Benashski, S. E., Do, K. T., Patel-King, R. S.,
et al. (1998). Cytoplasmic dynein contains a family of differentially expressed light
chains. Biochemistry 37, 15033−15041.
Krainc, D. (2010). Clearance of mutant proteins as a therapeutic target in neurode-
generative diseases. Arch Neurol 67, 388−392.
Kuhnlein, P., Sperfeld, A. D., Vanmassenhove, B., Van Deerlin, V., Lee, V. M., Trojanowski,
J. Q., et al. (2008). Two German kindreds with familial amyotrophic lateral sclerosis
due to TARDBP mutations. Arch Neurol 65, 1185−1189.
Kunzi, V., Glatzel, M., Nakano, M. Y., Greber, U. F., Van Leuven, F., & Aguzzi, A. (2002).
Unhampered prion neuroinvasion despite impaired fast axonal transport in
transgenic mice overexpressing four-repeat tau. J Neurosci 22, 7471−7477.
Kwiatkowski, T. J., Jr., Bosco, D. A., Leclerc, A. L., Tamrazian, E., Vanderburg, C. R., Russ, C.,
et al. (2009). Mutations in the FUS/TLS gene on chromosome 16 cause familial
amyotrophic lateral sclerosis. Science 323, 1205−1208.
Lach, B., Grimes, D., Benoit, B., & Minkiewicz-Janda, A. (1992). Caudate nucleus
pathology in Parkinson's disease: ultrastructural and biochemical findings in
biopsy material. Acta Neuropathol 83, 352−360.
Laforet, G. A., Sapp, E., Chase, K., McIntyre, C., Boyce, F. M., Campbell, M., et al. (2001).
Changes in cortical and striatal neurons predict behavioral and electrophysiological
abnormalities in a transgenic murine model of Huntington's disease. J Neurosci 21,
9112−9123.
Lagier-Tourenne, C., & Cleveland, D. W. (2009). Rethinking ALS: the FUS about TDP-43.
Cell 136, 1001−1004.
Lai, C., Lin, X., Chandran, J., Shim, H., Yang, W. J., & Cai, H. (2007). The G59S mutation in
p150(glued) causes dysfunction of dynactin in mice. J Neurosci 27, 13982−13990.
Laifenfeld, D., Patzek, L. J., McPhie, D. L., Chen, Y., Levites, Y., Cataldo, A. M., et al. (2007).
Rab5 mediates an amyloid precursor protein signaling pathway that leads to
apoptosis. J Neurosci 27, 7141−7153.
Laird, F. M., Farah, M. H., Ackerley, S., Hoke, A., Maragakis, N., Rothstein, J. D., et al.
(2008). Motor neuron disease occurring in a mutant dynactin mouse model is
characterized by defects in vesicular trafficking. J Neurosci 28, 1997−2005.
LaMonte, B. H., Wallace, K. E., Holloway, B. A., Shelly, S. S., Ascano, J., Tokito, M., et al.
(2002). Disruption of dynein/dynactin inhibits axonal transport in motor neurons
causing late-onset progressive degeneration. Neuron 34, 715−727.
La Spada, A. R., Wilson, E. M., Lubahn, D. B., Harding, A. E., & Fischbeck, K. H. (1991).
Androgen receptor gene mutations in X-linked spinal and bulbar muscular atrophy.
Nature 352, 77−79.
Lazarov, O., Lee, M., Peterson, D. A., & Sisodia, S. S. (2002). Evidence that synaptically
released beta-amyloid accumulates as extracellular deposits in the hippocampus of
transgenic mice. J Neurosci 22, 9785−9793.
 J. Eschbach, L. Dupuis / Pharmacology & Therapeutics 130 (2011) 348–363
Lazarov, O., Morfini, G. A., Lee, E. B., Farah, M. H., Szodorai, A., DeBoer, S. R., et al. (2005).
Axonal transport, amyloid precursor protein, kinesin-1, and the processing
apparatus: revisited. J Neurosci 25, 2386−2395.
Lee, H. J., Khoshaghideh, F., Lee, S., & Lee, S. J. (2006). Impairment of microtubule-dependent
trafficking by overexpression of alpha-synuclein. Eur J Neurosci 24, 3153−3162.
Lee, J. A., Beigneux, A., Ahmad, S. T., Young, S. G., & Gao, F. B. (2007). ESCRT-III dysfunc-
tion causes autophagosome accumulation and neurodegeneration. Curr Biol 17,
1561−1567.
Lee, S. J., Chae, C., & Wang, M. M. (2009). p150/glued modifies nuclear estrogen receptor
function. Mol Endocrinol 23, 620−629.
Lee, W. C., Yoshihara, M., & Littleton, J. T. (2004). Cytoplasmic aggregates trap
polyglutamine-containing proteins and block axonal transport in a Drosophila
model of Huntington's disease. Proc Natl Acad Sci U S A 101, 3224−3229.
Lees, A. J., Hardy, J., & Revesz, T. (2009). Parkinson's disease. Lancet 373, 2055−2066.
Lefebvre, S., Burglen, L., Reboullet, S., Clermont, O., Burlet, P., Viollet, L., et al. (1995).
Identification and characterization of a spinal muscular atrophy-determining gene.
Cell 80, 155−165.
Levy, J. R., & Holzbaur, E. L. (2006). Cytoplasmic dynein/dynactin function and
dysfunction in motor neurons. Int J Dev Neurosci 24, 103−111.
Levy, J. R., Sumner, C. J., Caviston, J. P., Tokito, M. K., Ranganathan, S., Ligon, L. A., et al.
(2006). A motor neuron disease-associated mutation in p150Glued perturbs
dynactin function and induces protein aggregation. J Cell Biol 172, 733−745.
Ligon, L. A., LaMonte, B. H., Wallace, K. E., Weber, N., Kalb, R. G., & Holzbaur, E. L. (2005).
Mutant superoxide dismutase disrupts cytoplasmic dynein in motor neurons.
Neuroreport 16, 533−536.
Lin, S. X., & Collins, C. A. (1992). Immunolocalization of cytoplasmic dynein to
lysosomes in cultured cells. J Cell Sci 101(Pt 1), 125−137.
Lin, X., Parisiadou, L., Gu, X. L., Wang, L., Shim, H., Sun, L., et al. (2009). Leucine-rich
repeat kinase 2 regulates the progression of neuropathology induced by
Parkinson's-disease-related mutant alpha-synuclein. Neuron 64, 807−827.
Lorenzo, D. N., Li, M. G., Mische, S. E., Armbrust, K. R., Ranum, L. P., & Hays, T. S. (2010).
Spectrin mutations that cause spinocerebellar ataxia type 5 impair axonal transport
and induce neurodegeneration in Drosophila. J Cell Biol 189, 143−158.
Magnani, E., Fan, J., Gasparini, L., Golding, M., Williams, M., Schiavo, G., et al. (2007).
Interaction of tau protein with the dynactin complex. EMBO J 26, 4546−4554.
Mallik, R., Carter, B. C., Lex, S. A., King, S. J., & Gross, S. P. (2004). Cytoplasmic dynein
functions as a gear in response to load. Nature 427, 649−652.
Mallik, R., & Gross, S. P. (2004). Molecular motors: strategies to get along. Curr Biol 14,
R971−R982.
Marques, V. D., Barreira, A. A., Davis, M. B., Abou-Sleiman, P. M., Silva, W. A., Jr., Zago, M. A.,
et al. (2006). Expanding the phenotypes of the Pro56Ser VAPB mutation:
proximal SMA with dysautonomia. Muscle Nerve 34, 731−739.
Martinez-Vicente, M., Talloczy, Z., Wong, E., Tang, G., Koga, H., Kaushik, S., et al. (2010).
Cargo recognition failure is responsible for inefficient autophagy in Huntington's
disease. Nat Neurosci 13, 567−576.
Matanis, T., Akhmanova, A., Wulf, P., Del Nery, E., Weide, T., Stepanova, T., et al. (2002).
Bicaudal-D regulates COPI-independent Golgi-ER transport by recruiting the
dynein–dynactin motor complex. Nat Cell Biol 4, 986−992.
Matsuda, N., Sato, S., Shiba, K., Okatsu, K., Saisho, K., Gautier, C. A., et al. (2010). PINK1
stabilized by mitochondrial depolarization recruits Parkin to damaged mitochon-
dria and activates latent Parkin for mitophagy. J Cell Biol 189, 211−221.
McCray, B. A., Skordalakes, E., & Taylor, J. P. (2010). Disease mutations in Rab7 result in
unregulated nucleotide exchange and inappropriate activation. Hum Mol Genet 19,
1033−1047.
Middleton, F. A., & Strick, P. L. (2000). Basal ganglia and cerebellar loops: motor and
cognitive circuits. Brain Res Brain Res Rev 31, 236−250.
Mikami, A., Tynan, S. H., Hama, T., Luby-Phelps, K., Saito, T., Crandall, J. E., et al. (2002).
Molecular structure of cytoplasmic dynein 2 and its distribution in neuronal and
ciliated cells. J Cell Sci 115, 4801−4808.
Millecamps, S., Salachas, F., Cazeneuve, C., Gordon, P., Bricka, B., Camuzat, A., et al.
(2010). SOD1, ANG, VAPB, TARDBP, and FUS mutations in familial amyotrophic
lateral sclerosis: genotype-phenotype correlations. J Med Genet 47, 554−560.
Miller, K. E., & Sheetz, M. P. (2004). Axonal mitochondrial transport and potential are
correlated. J Cell Sci 117, 2791−2804.
Misko, A., Jiang, S., Wegorzewska, I., Milbrandt, J., & Baloh, R. H. (2010). Mitofusin 2 is
necessary for transport of axonal mitochondria and interacts with the Miro/Milton
complex. J Neurosci 30, 4232−4240.
Morfini, G., Pigino, G., Opalach, K., Serulle, Y., Moreira, J. E., Sugimori, M., et al. (2007). 1-
Methyl-4-phenylpyridinium affects fast axonal transport by activation of caspase
and protein kinase C. Proc Natl Acad Sci U S A 104, 2442−2447.
Morfini, G., Pigino, G., Szebenyi, G., You, Y., Pollema, S., & Brady, S. T. (2006). JNK
mediates pathogenic effects of polyglutamine-expanded androgen receptor on fast
axonal transport. Nat Neurosci 9, 907−916.
Morfini, G. A., Burns, M., Binder, L. I., Kanaan, N. M., LaPointe, N., Bosco, D. A., et al. (2009).
Axonal transport defects in neurodegenerative diseases. J Neurosci 29, 12776−12786.
Moya, K. L., Hassig, R., Creminon, C., Laffont, I., & Di Giamberardino, L. (2004). Enhanced
detection and retrograde axonal transport of PrPc in peripheral nerve. J Neurochem
88, 155−160.
Munch, C., Sedlmeier, R., Meyer, T., Homberg, V., Sperfeld, A. D., Kurt, A., et al. (2004).
Point mutations of the p150 subunit of dynactin (DCTN1) gene in ALS. Neurology
63, 724−726.
Narendra, D., Tanaka, A., Suen, D. F., & Youle, R. J. (2008). Parkin is recruited selectively
to impaired mitochondria and promotes their autophagy. J Cell Biol 183, 795−803.
Narendra, D. P., Jin, S. M., Tanaka, A., Suen, D. F., Gautier, C. A., Shen, J., et al. (2010).
PINK1 is selectively stabilized on impaired mitochondria to activate Parkin. PLoS
Biol 8, e1000298.
361
Neumann, M., Sampathu, D. M., Kwong, L. K., Truax, A. C., Micsenyi, M. C., Chou, T. T.,
et al. (2006). Ubiquitinated TDP-43 in frontotemporal lobar degeneration and
amyotrophic lateral sclerosis. Science 314, 130−133.
Nguyen, L., Humbert, S., Saudou, F., & Chariot, A. (2010). Elongator - an emerging role in
neurological disorders. Trends Mol Med 16, 1−6.
Nishimura, A. L., Mitne-Neto, M., Silva, H. C., Richieri-Costa, A., Middleton, S., Cascio, D.,
et al. (2004). A mutation in the vesicle-trafficking protein VAPB causes late-onset
spinal muscular atrophy and amyotrophic lateral sclerosis. Am J Hum Genet 75,
822−831.
Olzmann, J. A., Li, L., Chudaev, M. V., Chen, J., Perez, F. A., Palmiter, R. D., et al. (2007).
Parkin-mediated K63-linked polyubiquitination targets misfolded DJ-1 to aggre-
somes via binding to HDAC6. J Cell Biol 178, 1025−1038.
Ori-McKenney, K. M., Xu, J., Gross, S. P., & Vallee, R. B. (2010). A cytoplasmic dynein tail
mutation impairs motor processivity. Nat Cell Biol 12, 1228−1234.
Otomo, A., Hadano, S., Okada, T., Mizumura, H., Kunita, R., Nishijima, H., et al. (2003).
ALS2, a novel guanine nucleotide exchange factor for the small GTPase Rab5, is
implicated in endosomal dynamics. Hum Mol Genet 12, 1671−1687.
Ou, C. Y., Poon, V. Y., Maeder, C. I., Watanabe, S., Lehrman, E. K., Fu, A. K., et al. (2010).
Two cyclin-dependent kinase pathways are essential for polarized trafficking of
presynaptic components. Cell 141, 846−858.
Palop, J. J., & Mucke, L. (2010). Amyloid-beta-induced neuronal dysfunction in
Alzheimer's disease: from synapses toward neural networks. Nat Neurosci 13,
812−818.
Pandey, U. B., Nie, Z., Batlevi, Y., McCray, B. A., Ritson, G. P., Nedelsky, N. B., et al. (2007).
HDAC6 rescues neurodegeneration and provides an essential link between
autophagy and the UPS. Nature 447, 859−863.
Pardo, R., Molina-Calavita, M., Poizat, G., Keryer, G., Humbert, S., & Saudou, F. (2010).
pARIS-htt: an optimised expression platform to study huntingtin reveals functional
domains required for vesicular trafficking. Mol Brain 3, 17.
Parkinson, N., Ince, P. G., Smith, M. O., Highley, R., Skibinski, G., Andersen, P. M., et al.
(2006). ALS phenotypes with mutations in CHMP2B (charged multivesicular body
protein 2B). Neurology 67, 1074−1077.
Paschal, B. M., Shpetner, H. S., & Vallee, R. B. (1987). MAP 1C is a microtubule-activated ATPase
which translocates microtubules in vitro and has dynein-like properties. J Cell Biol 105,
1273−1282.
Paschal, B. M., & Vallee, R. B. (1987). Retrograde transport by the microtubule-
associated protein MAP 1 C. Nature 330, 181−183.
Peretti, D., Dahan, N., Shimoni, E., Hirschberg, K., & Lev, S. (2008). Coordinated lipid
transfer between the endoplasmic reticulum and the Golgi complex requires the
VAP proteins and is essential for Golgi-mediated transport. Mol Biol Cell 19,
3871−3884.
Perez-Olle, R., Jones, S. T., & Liem, R. K. (2004). Phenotypic analysis of neurofilament
light gene mutations linked to Charcot–Marie–Tooth disease in cell culture models.
Hum Mol Genet 13, 2207−2220.
Perkins, E. M., Clarkson, Y. L., Sabatier, N., Longhurst, D. M., Millward, C. P., Jack, J., et al.
(2010). Loss of beta-III spectrin leads to Purkinje cell dysfunction recapitulating the
behavior and neuropathology of spinocerebellar ataxia type 5 in humans. J Neurosci
30, 4857−4867.
Perlson, E., Jeong, G. B., Ross, J. L., Dixit, R., Wallace, K. E., Kalb, R. G., et al. (2009). A
switch in retrograde signaling from survival to stress in rapid-onset neurodegen-
eration. J Neurosci 29, 9903−9917.
Pfarr, C. M., Coue, M., Grissom, P. M., Hays, T. S., Porter, M. E., & McIntosh, J. R. (1990).
Cytoplasmic dynein is localized to kinetochores during mitosis. Nature 345,
263−265.
Pfister, K. K., Fisher, E. M., Gibbons, I. R., Hays, T. S., Holzbaur, E. L., McIntosh, J. R., et al.
(2005). Cytoplasmic dynein nomenclature. J Cell Biol 171, 411−413.
Pfister, K. K., Shah, P. R., Hummerich, H., Russ, A., Cotton, J., Annuar, A. A., et al. (2006).
Genetic analysis of the cytoplasmic dynein subunit families. PLoS Genet 2, e1.
Pigino, G., Morfini, G., Atagi, Y., Deshpande, A., Yu, C., Jungbauer, L., et al. (2009).
Disruption of fast axonal transport is a pathogenic mechanism for intraneuronal
amyloid beta. Proc Natl Acad Sci U S A 106, 5907−5912.
Pilling, A. D., Horiuchi, D., Lively, C. M., & Saxton, W. M. (2006). Kinesin-1 and Dynein
are the primary motors for fast transport of mitochondria in Drosophila motor
axons. Mol Biol Cell 17, 2057−2068.
Porter, M. E., Bower, R., Knott, J. A., Byrd, P., & Dentler, W. (1999). Cytoplasmic dynein
heavy chain 1b is required for flagellar assembly in Chlamydomonas. Mol Biol Cell
10, 693−712.
Puls, I., Jonnakuty, C., LaMonte, B. H., Holzbaur, E. L., Tokito, M., Mann, E., et al. (2003).
Mutant dynactin in motor neuron disease. Nat Genet 33, 455−456.
Puls, I., Oh, S. J., Sumner, C. J., Wallace, K. E., Floeter, M. K., Mann, E. A., et al. (2005).
Distal spinal and bulbar muscular atrophy caused by dynactin mutation. Ann Neurol
57, 687−694.
Raiborg, C., & Stenmark, H. (2009). The ESCRT machinery in endosomal sorting of
ubiquitylated membrane proteins. Nature 458, 445−452.
Ravikumar, B., Acevedo-Arozena, A., Imarisio, S., Berger, Z., Vacher, C., O'Kane, C. J., et al.
(2005). Dynein mutations impair autophagic clearance of aggregate-prone
proteins. Nat Genet 37, 771−776.
Raychaudhuri, S., & Prinz, W. A. (2010). The Diverse Functions of Oxysterol-Binding
Proteins. Annu Rev Cell Dev Biol 26, 157−177.
Reed, N. A., Cai, D., Blasius, T. L., Jih, G. T., Meyhofer, E., Gaertig, J., et al. (2006).
Microtubule acetylation promotes kinesin-1 binding and transport. Curr Biol 16,
2166−2172.
Regehr, W. G., Carey, M. R., & Best, A. R. (2009). Activity-dependent regulation of
synapses by retrograde messengers. Neuron 63, 154−170.
Rishal, I., & Fainzilber, M. (2010). Retrograde signaling in axonal regeneration. Exp
Neurol 223, 5−10.
362 J. Eschbach, L. Dupuis / Pharmacology & Therapeutics 130 (2011) 348–363
Rocha, N., Kuijl, C., van der Kant, R., Janssen, L., Houben, D., Janssen, H., et al. (2009).
Cholesterol sensor ORP1L contacts the ER protein VAP to control Rab7-RILP-p150
Glued and late endosome positioning. J Cell Biol 185, 1209−1225.
Ross, J. L., Wallace, K., Shuman, H., Goldman, Y. E., & Holzbaur, E. L. (2006). Processive
bidirectional motion of dynein–dynactin complexes in vitro. Nat Cell Biol 8, 562−570.
Ross, J. L., Ali, M. Y., & Warshaw, D. M. (2008a). Cargo transport: molecular motors
navigate a complex cytoskeleton. Curr Opin Cell Biol 20, 41−47.
Ross, O. A., Braithwaite, A. T., Skipper, L. M., Kachergus, J., Hulihan, M. M., Middleton, F. A.,
et al. (2008b). Genomic investigation of alpha-synuclein multiplication and
parkinsonism. Ann Neurol 63, 743−750.
Rubinsztein, D. C., Barton, D. E., Davison, B. C., & Ferguson-Smith, M. A. (1993). Analysis
of the huntingtin gene reveals a trinucleotide-length polymorphism in the region
of the gene that contains two CCG-rich stretches and a correlation between
decreased age of onset of Huntington's disease and CAG repeat number. Hum Mol
Genet 2, 1713−1715.
Rui, Y., Tiwari, P., Xie, Z., & Zheng, J. Q. (2006). Acute impairment of mitochondrial
trafficking by beta-amyloid peptides in hippocampal neurons. J Neurosci 26,
10480−10487.
Rutherford, N. J., Zhang, Y. J., Baker, M., Gass, J. M., Finch, N. A., Xu, Y. F., et al. (2008).
Novel mutations in TARDBP (TDP-43) in patients with familial amyotrophic lateral
sclerosis. PLoS Genet 4, e1000193.
Saha, A. R., Hill, J., Utton, M. A., Asuni, A. A., Ackerley, S., Grierson, A. J., et al. (2004).
Parkinson's disease alpha-synuclein mutations exhibit defective axonal transport
in cultured neurons. J Cell Sci 117, 1017−1024.
Saksena, S., Sun, J., Chu, T., & Emr, S. D. (2007). ESCRTing proteins in the endocytic
pathway. Trends Biochem Sci 32, 561−573.
Sasaki, S., & Iwata, M. (1996). Impairment of fast axonal transport in the proximal axons
of anterior horn neurons in amyotrophic lateral sclerosis. Neurology 47, 535−540.
Sasaki, S., Warita, H., Abe, K., & Iwata, M. (2005). Impairment of axonal transport in the
axon hillock and the initial segment of anterior horn neurons in transgenic mice
with a G93A mutant SOD1 gene. Acta Neuropathol 110, 48−56.
Satoh, D., Sato, D., Tsuyama, T., Saito, M., Ohkura, H., Rolls, M. M., et al. (2008). Spatial
control of branching within dendritic arbors by dynein-dependent transport of
Rab5-endosomes. Nat Cell Biol 10, 1164−1171.
Schnapp, B. J., & Reese, T. S. (1989). Dynein is the motor for retrograde axonal transport
of organelles. Proc Natl Acad Sci U S A 86, 1548−1552.
Schroer, T. A. (2004). Dynactin. Annu Rev Cell Dev Biol 20, 759−779.
Schroer, T. A., Steuer, E. R., & Sheetz, M. P. (1989). Cytoplasmic dynein is a minus end-
directed motor for membranous organelles. Cell 56, 937−946.
Serulle, Y., Morfini, G., Pigino, G., Moreira, J. E., Sugimori, M., Brady, S. T., et al. (2007). 1-
Methyl-4-phenylpyridinium induces synaptic dysfunction through a pathway
involving caspase and PKCdelta enzymatic activities. Proc Natl Acad Sci U S A 104,
2437−2441.
Shi, P., Strom, A. L., Gal, J., & Zhu, H. (2010). Effects of ALS-related SOD1 mutants on
dynein- and KIF5-mediated retrograde and anterograde axonal transport. Biochim
Biophys Acta 1802, 707−716.
Shrum, C. K., Defrancisco, D., & Meffert, M. K. (2009). Stimulated nuclear translocation
of NF-kappaB and shuttling differentially depend on dynein and the dynactin
complex. Proc Natl Acad Sci U S A 106, 2647−2652.
Simpson, C. L., Lemmens, R., Miskiewicz, K., Broom, W. J., Hansen, V. K., van Vught, P. W.,
et al. (2009). Variants of the elongator protein 3 (ELP3) gene are associated with
motor neuron degeneration. Hum Mol Genet 18, 472−481.
Sinadinos, C., Burbidge-King, T., Soh, D., Thompson, L. M., Marsh, J. L., Wyttenbach, A.,
et al. (2009). Live axonal transport disruption by mutant huntingtin fragments in
Drosophila motor neuron axons. Neurobiol Dis 34, 389−395.
Sisodia, S. S., Koo, E. H., Hoffman, P. N., Perry, G., & Price, D. L. (1993). Identification and
transport of full-length amyloid precursor proteins in rat peripheral nervous
system. J Neurosci 13, 3136−3142.
Skibinski, G., Parkinson, N. J., Brown, J. M., Chakrabarti, L., Lloyd, S. L., Hummerich, H.,
et al. (2005). Mutations in the endosomal ESCRTIII-complex subunit CHMP2B in
frontotemporal dementia. Nat Genet 37, 806−808.
Spinosa, M. R., Progida, C., De Luca, A., Colucci, A. M., Alifano, P., & Bucci, C. (2008).
Functional characterization of Rab7 mutant proteins associated with Charcot–
Marie–Tooth type 2B disease. J Neurosci 28, 1640−1648.
Splinter, D., Tanenbaum, M. E., Lindqvist, A., Jaarsma, D., Flotho, A., Yu, K. L., et al. (2010).
Bicaudal D2, dynein, and kinesin-1 associate with nuclear pore complexes and
regulate centrosome and nuclear positioning during mitotic entry. PLoS Biol 8,
e1000350.
Sreedharan, J., Blair, I. P., Tripathi, V. B., Hu, X., Vance, C., Rogelj, B., et al. (2008). TDP-43
mutations in familial and sporadic amyotrophic lateral sclerosis. Science 319,
1668−1672.
Stankewich, M. C., Gwynn, B., Ardito, T., Ji, L., Kim, J., Robledo, R. F., et al. (2010).
Targeted deletion of betaIII spectrin impairs synaptogenesis and generates ataxic
and seizure phenotypes. Proc Natl Acad Sci U S A 107, 6022−6027.
Stokin, G. B., Almenar-Queralt, A., Gunawardena, S., Rodrigues, E. M., Falzone, T., Kim, J.,
et al. (2008). Amyloid precursor protein-induced axonopathies are independent of
amyloid-beta peptides. Hum Mol Genet 17, 3474−3486.
Stokin, G. B., & Goldstein, L. S. (2006). Axonal transport and Alzheimer's disease. Annu
Rev Biochem 75, 607−627.
Stokin, G. B., Lillo, C., Falzone, T. L., Brusch, R. G., Rockenstein, E., Mount, S. L., et al.
(2005). Axonopathy and transport deficits early in the pathogenesis of Alzheimer's
disease. Science 307, 1282−1288.
Strom, A. L., Shi, P., Zhang, F., Gal, J., Kilty, R., Hayward, L. J., et al. (2008). Interaction of
amyotrophic lateral sclerosis (ALS)-related mutant copper-zinc superoxide
dismutase with the dynein–dynactin complex contributes to inclusion formation.
J Biol Chem 283, 22795−22805.
Stuffers, S., Brech, A., & Stenmark, H. (2009). ESCRT proteins in physiology and disease.
Exp Cell Res 315, 1619−1626.
Szebenyi, G., Morfini, G. A., Babcock, A., Gould, M., Selkoe, K., Stenoien, D. L., et al.
(2003). Neuropathogenic forms of huntingtin and androgen receptor inhibit fast
axonal transport. Neuron 40, 41−52.
Takahashi, Y., Edamatsu, M., & Toyoshima, Y. Y. (2004). Multiple ATP-hydrolyzing sites
that potentially function in cytoplasmic dynein. Proc Natl Acad Sci U S A 101,
12865−12869.
Tang, B. L. (2009). Neuronal protein trafficking associated with Alzheimer disease: from
APP and BACE1 to glutamate receptors. Cell Adhes Migr 3, 118−128.
Terasaki, M. (1990). Recent progress on structural interactions of the endoplasmic
reticulum. Cell Motil Cytoskeleton 15, 71−75.
Teuling, E., van Dis, V., Wulf, P. S., Haasdijk, E. D., Akhmanova, A., Hoogenraad, C. C., et al.
(2008). A novel mouse model with impaired dynein/dynactin function develops
amyotrophic lateral sclerosis (ALS)-like features in motor neurons and improves
lifespan in SOD1-ALS mice. Hum Mol Genet 17, 2849−2862.
Thayanidhi, N., Helm, J. R., Nycz, D. C., Bentley, M., Liang, Y., & Hay, J. C. (2010). Alpha-
synuclein delays endoplasmic reticulum (ER)-to-Golgi transport in mammalian
cells by antagonizing ER/Golgi SNAREs. Mol Biol Cell 21, 1850−1863.
Ticozzi, N., Silani, V., Leclerc, A. L., Keagle, P., Gellera, C., Ratti, A., et al. (2009). Analysis of
FUS gene mutation in familial amyotrophic lateral sclerosis within an Italian cohort.
Neurology 73(15), 1180−1185.
Topp, J. D., Gray, N. W., Gerard, R. D., & Horazdovsky, B. F. (2004). Alsin is a Rab5 and
Rac1 guanine nucleotide exchange factor. J Biol Chem 279, 24612−24623.
Trushina, E., Dyer, R. B., Badger, J. D., 2nd, Ure, D., Eide, L., Tran, D. D., et al. (2004).
Mutant huntingtin impairs axonal trafficking in mammalian neurons in vivo and in
vitro. Mol Cell Biol 24, 8195−8209.
Twig, G., Elorza, A., Molina, A. J., Mohamed, H., Wikstrom, J. D., Walzer, G., et al. (2008).
Fission and selective fusion govern mitochondrial segregation and elimination by
autophagy. EMBO J 27, 433−446.
Urwin, H., Authier, A., Nielsen, J. E., Metcalf, D., Powell, C., Froud, K., et al. (2010).
Disruption of endocytic trafficking in frontotemporal dementia with CHMP2B
mutations. Hum Mol Genet 19, 2228−2238.
van der Zee, J., Urwin, H., Engelborghs, S., Bruyland, M., Vandenberghe, R., Dermaut, B.,
et al. (2008). CHMP2B C-truncating mutations in frontotemporal lobar degener-
ation are associated with an aberrant endosomal phenotype in vitro. Hum Mol
Genet 17, 313−322.
van Spronsen, M., & Hoogenraad, C. C. (2010). Synapse pathology in psychiatric and
neurologic disease. Curr Neurol Neurosci Rep 10, 207−214.
Vaughan, K. T. (2005). Microtubule plus ends, motors, and traffic of Golgi membranes.
Biochim Biophys Acta 1744, 316−324.
Vaughan, K. T., & Vallee, R. B. (1995). Cytoplasmic dynein binds dynactin through a
direct interaction between the intermediate chains and p150Glued. J Cell Biol 131,
1507−1516.
Vavlitou, N., Sargiannidou, I., Markoullis, K., Kyriacou, K., Scherer, S. S., & Kleopa, K. A.
(2010). Axonal pathology precedes demyelination in a mouse model of X-linked
demyelinating/type I Charcot–Marie–Tooth neuropathy. J Neuropathol Exp Neurol
69, 945−958.
Verhoeven, K., De Jonghe, P., Coen, K., Verpoorten, N., Auer-Grumbach, M., Kwon, J. M.,
et al. (2003). Mutations in the small GTP-ase late endosomal protein RAB7 cause
Charcot–Marie–Tooth type 2B neuropathy. Am J Hum Genet 72, 722−727.
Vives-Bauza, C., Zhou, C., Huang, Y., Cui, M., de Vries, R. L., Kim, J., et al. (2010). PINK1-
dependent recruitment of Parkin to mitochondria in mitophagy. Proc Natl Acad Sci U S A
107(1), 378−383.
Vives-Bauza, C., Zhou, C., Huang, Y., Cui, M., de Vries, R. L., Kim, J., et al. (2010). PINK1-
dependent recruitment of Parkin to mitochondria in mitophagy. Proc Natl Acad Sci
U S A 107, 378−383.
Vossel, K. A., Zhang, K., Brodbeck, J., Daub, A. C., Sharma, P., Finkbeiner, S., et al. (2010).
Tau Reduction Prevents A{beta}-Induced Defects in Axonal Transport. Science 330
(6001), 198.
Wagner, O. I., Ascano, J., Tokito, M., Leterrier, J. F., Janmey, P. A., & Holzbaur, E. L. (2004).
The interaction of neurofilaments with the microtubule motor cytoplasmic dynein.
Mol Biol Cell 15, 5092−5100.
Walker, F. O. (2007). Huntington's disease. Lancet 369, 218−228.
Weydt, P., Pineda, V. V., Torrence, A. E., Libby, R. T., Satterfield, T. F., Lazarowski, E. R.,
et al. (2006). Thermoregulatory and metabolic defects in Huntington's disease
transgenic mice implicate PGC-1alpha in Huntington's disease neurodegeneration.
Cell Metab 4, 349−362.
Wikstrom, J. D., Twig, G., & Shirihai, O. S. (2009). What can mitochondrial heterogeneity
tell us about mitochondrial dynamics and autophagy? Int J Biochem Cell Biol 41,
1914−1927.
Williamson, T. L., & Cleveland, D. W. (1999). Slowing of axonal transport is a very early event
in the toxicity of ALS-linked SOD1 mutants to motor neurons. Nat Neurosci 2, 50−56.
Winslow, A. R., Chen, C. W., Corrochano, S., Acevedo-Arozena, A., Gordon, D. E., Peden, A. A.,
et al. (2010). alpha-Synuclein impairs macroautophagy: implications for Parkinson's
disease. J Cell Biol 190, 1023−1037.
Wong, E., & Cuervo, A. M. (2010). Autophagy gone awry in neurodegenerative diseases.
Nat Neurosci 13, 805−811.
Yang, Y., Hentati, A., Deng, H. X., Dabbagh, O., Sasaki, T., Hirano, M., et al. (2001). The
gene encoding alsin, a protein with three guanine-nucleotide exchange factor
domains, is mutated in a form of recessive amyotrophic lateral sclerosis. Nat Genet
29, 160−165.
Yokoseki, A., Shiga, A., Tan, C. F., Tagawa, A., Kaneko, H., Koyama, A., et al. (2008).
TDP-43 mutation in familial amyotrophic lateral sclerosis. Ann Neurol 63, 538−542.
Yoshida, T., Takanari, H., & Izutsu, K. (1992). Distribution of cytoplasmic and axonemal
dyneins in rat tissues. J Cell Sci 101(Pt 3), 579−587.
 J. Eschbach, L. Dupuis / Pharmacology & Therapeutics 130 (2011) 348–363
Yudin, D., Hanz, S., Yoo, S., Iavnilovitch, E., Willis, D., Gradus, T., et al. (2008). Localized
regulation of axonal RanGTPase controls retrograde injury signaling in peripheral
nerve. Neuron 59, 241−252.
Zala, D., Colin, E., Rangone, H., Liot, G., Humbert, S., & Saudou, F. (2008). Phosphory-
lation of mutant huntingtin at S421 restores anterograde and retrograde transport
in neurons. Hum Mol Genet 17, 3837−3846.
Zhang, B., Tu, P., Abtahian, F., Trojanowski, J. Q., & Lee, V. M. (1997). Neurofilaments and
orthograde transport are reduced in ventral root axons of transgenic mice that
express human SOD1 with a G93A mutation. J Cell Biol 139, 1307−1315.
Zhang, F., Strom, A. L., Fukada, K., Lee, S., Hayward, L. J., & Zhu, H. (2007). Interaction
between familial amyotrophic lateral sclerosis (ALS)-linked SOD1 mutants and the
dynein complex. J Biol Chem 282, 16691−16699.
Zhang, X., Lei, K., Yuan, X., Wu, X., Zhuang, Y., Xu, T., et al. (2009). SUN1/2 and Syne/
Nesprin-1/2 complexes connect centrosome to the nucleus during neurogenesis
and neuronal migration in mice. Neuron 64, 173−187.
363
Zheng, Y., Wildonger, J., Ye, B., Zhang, Y., Kita, A., Younger, S. H., et al. (2008). Dynein is
required for polarized dendritic transport and uniform microtubule orientation in
axons. Nat Cell Biol 10, 1172−1180.
Zhou, X., Ikenoue, T., Chen, X., Li, L., Inoki, K., & Guan, K. L. (2009). Rheb controls
misfolded protein metabolism by inhibiting aggresome formation and autophagy.
Proc Natl Acad Sci U S A 106, 8923−8928.
Zuccato, C., Ciammola, A., Rigamonti, D., Leavitt, B. R., Goffredo, D., Conti, L., et al.
(2001). Loss of huntingtin-mediated BDNF gene transcription in Huntington's
disease. Science 293, 493−498.
Zweifel, L. S., Kuruvilla, R., & Ginty, D. D. (2005). Functions and mechanisms of
retrograde neurotrophin signalling. Nat Rev Neurosci 6, 615−625.