General and Comparative Endocrinology 172 (2011) 39–43

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General and Comparative Endocrinology

journal homepage: www.elsevier.com/locate/ygcen

Review

The role of ubiquitin–proteasome system in ageing

Peter Löw ⇑
Department of Anatomy, Cell and Developmental Biology, Eötvös Loránd University, Budapest, Hungary

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

Article history: Maintenance of cellular homeostasis influences ageing and it is determined by several factors, including
Available online 13 February 2011 efficient proteolysis of damaged proteins. The ubiquitin–proteasome system is the major protein degra-
dation pathway in the cell. Specifically, the proteasome is responsible for clearance of abnormal, dena-
Keywords: tured or in general damaged proteins as well as for the regulated degradation of short-lived proteins.
Insulin In this review the involvement of the ubiquitin–proteasome pathway in protein degradation at different
Insulin-like growth factor levels of cellular life is discussed in relation with ageing. Though the exact underlying mechanism is
Ubiquitin
unclear, an age-related decrease in proteasome activity weakens cellular capacity to remove oxidatively
Proteasome
Ageing
modified proteins and favours the development of diseases. Up-regulation of proteasome activity is char-
acteristic of muscle wasting conditions, but may not be rate limiting. Meanwhile, enhanced presence of
immunoproteasomes in ageing brain and muscle tissue could reflect a persistent inflammatory defence
and anti-stress mechanism. Insulin/IGF-1 signalling regulates ageing in worms, flies and mammals.
The insulin/IGF-1 receptor inhibits the forkhead transcription factor, FoxO through activating a cascade
of conserved kinases. Longevity increases when FoxO becomes activated in response to reduced insu-
lin/IGF-1 signalling. The ubiquitin–proteasome system plays a major role in signal transduction associ-
ated with stress and ageing. The understanding of specific proteolytic targeting paves the way for a
new generation of active molecules that may control particular steps of normal and pathological ageing.
Ó 2011 Elsevier Inc. All rights reserved.

1. Introduction and ageing associated diseases. Since in most instances ubiquityla-

Protein degradation by the ubiquitin–proteasome system is an
essential cellular mechanism that has come into focus of ageing re-
search recently. One of the most important machineries for degra-
dation of endogenous proteins is the proteasome, whose activity
decreases during the ageing process. Several major ageing related
diseases have been characterised as protein degradation failures.
Two major pathways accomplish regulated protein catabolism
in eukaryotic cells: the ubiquitin–proteasome system (UPS) and
the autophagy–lysosomal system. The UPS serves as the primary
route for degradation for thousands of short-lived proteins and
many regulatory proteins. UPS-mediated catabolism is also essen-
tial to maintain amino acid pools in acute starvation and contrib-
utes to the degradation of defective proteins. Autophagy, by
contrast, is primarily responsible for degrading long-lived proteins
and maintaining amino acid pools in chronic starvation.
During the recent years evidence has increased that proteasome
activity is decreased during the ageing process in various model
systems and that these changes might be causally related to ageing
⇑ Address: Eötvös Loránd University, Department of Anatomy, Cell and Develop-
mental Biology, Pazmany Peter setany 1/C, H-1117 Budapest, Hungary. Fax: +36 1
381 2184.
E-mail address: peterlow@elte.hu
tion is the primary event in target selection, the system of ubiqui-
tylation and deubiquitylation might be of similar importance.
2. The ubiquitin–proteasome system
The majority of cellular proteins are degraded by the UPS, which
consists of both substrate-recruiting and substrate-degrading
machinery. The former is composed of three enzymes, the first of
which (E1) activates the polypeptide ubiquitin in an ATP depen-
dent manner, enabling its transfer onto a ubiquitin carrier enzyme
(E2). Activated ubiquitin is further transferred by a ubiquitin pro-
tein ligase (E3) to a substrate protein [11]. The substrate-recruiting
machinery then catalyses the formation of an isopeptide bond be-
tween the C-terminal glycine residue of ubiquitin and the e-amino
group of a substrate protein lysine residue. Repeated addition of
ubiquitin moieties onto the first results in a polyubiquitylated sub-
strate protein that is recognised by the proteolytic machinery of
the UPS, the 26S proteasome. The requirement for the addition of
multiple ubiquitin molecules may be part of a proof-reading mech-
anism, as a large number of deubiquitylating enzymes (DUBs) are
also found within cells [29]. DUBs remove ubiquitin molecules be-
fore a sufficiently large branch structure has been synthesised to
activate proteasomal destruction (Fig. 1).

0016-6480/$ - see front matter Ó 2011 Elsevier Inc. All rights reserved.
doi:10.1016/j.ygcen.2011.02.005
40 P. Löw / General and Comparative Endocrinology 172 (2011) 39–43
Fig. 1. The ubiquitylation cascade. Ubiquitin (Ub) is a small 8 kDa protein, which is
first transferred to the ubiquitin-activating enzyme, E1, in an ATP dependent
manner. This activated ubiquitin is then transferred to the ubiquitin conjugating
enzyme, E2. Finally, the ubiquitin is covalently attached to the target protein by E3
ubiquitin ligase, leading to the formation of a polyubiquitin chain. The polyubiq-
uitylated protein is recognised by the 26S proteasome, and is destroyed in an ATP-
dependent manner. Deubiquitinating enzymes (DUB) can rescue proteins from
degradation and recycle ubiquitin or ubiquitin oligomers from ubiquitin–protein
conjugates. (Ub, ubiquitin; E1, ubiquitin-activating enzyme; E2, ubiquitin-conju-
gating enzyme; E3, ubiquitin ligase; DUB, deubiquitinating enzyme.)
The overall shape of the 20S proteasome is an elongated cylin-
der with large central cavities and narrow constrictions. The seven
different a-subunits are located at the ends, whereas the seven dif-
ferent b-subunits form the two inner rings. a-ring is closed by the
amino-terminal extensions of the a-subunits, whereas the b-ring
has an open space in its centre. There are two antichambers inside
the proteasome and a central catalytic chamber. Only three b sub-
units are active among the b subunits in both b rings. Subunits b1,
b2 and b5 of both adjacent b-rings expose their proteolytically
active sites, exhibiting caspase-like, trypsin-like and chymotryp-
sin-like cleavage specificity, respectively. Other b-subunits form
the active pocket for them. In mammalian cells, the 20S core is
found associated with activator complexes PA700 (19S) or PA28
(11S) [6]. PA700 contains at least 18 subunits, including six ATPas-
es in its ‘‘base’’, that exert a chaperone-like activity and can unfold
proteins prior to entry in the proteolytic chamber, and eight sub-
units in its ‘‘lid’’, that recognise the poly-ubiquitin (poly-Ub) sig-
nals [28]. When capped with PA700, the 20S proteasome forms
the 26S complex, which is the competent structure for Ub-medi-
ated proteolysis. Binding of the substrate protein to the protea-
some is followed by protein unfolding by the half-dozen ATPases
that encircle the pore of the proteasome catalytic core, and trans-
location of the unfolded protein into the central proteolytic cham-
ber, where it is cleaved into short peptides. The 20S proteasome in
turn, works independently of ATP and ubiquitin and has been
implicated in the degradation of damaged or unfolded proteins.
26S proteasome activity can be identified as the ATP-associated
activity. ATP stabilises the 26S complex and allows the opening
of channels in the rings of the 20S core by ATPases located in the
19S regulatory particle [17] (Fig. 2).
Proteasome has also been implicated in antigen presentation
process and immune response, mainly through immunoprotea-
somes. In this proteasome type, the constitutively expressed b1,
b2 and b5 subunits are substituted during de novo proteasome bio-
Fig. 2. Structure of 20S, 26S and immunoproteasome. 26S proteasome is a large
multisubunit protease complex that selectively degrades polyubiquitylated pro-
teins. It is composed of two subcomplexes: a barrel-shaped 20S core particle
containing the protease active sites and two 19S regulatory particles that cap the
barrel and control access of substrates to the core. The 20S particle consists of four
axially stacked heptameric rings, two inner b-rings and two outer a-rings, forming
three continuous chambers inside. This structure keeps the proteolytic active sites,
located at the N-termini of three of the seven b-subunits, sequestered in the central
chamber and prevents unregulated substrate degradation. The 19S regulatory
particles are composed of approximately 20 subunits which form a ‘‘lid’’ and a
‘‘base’’. During host infection cellular stimulation with interferon-c results in the
new synthesis of immunoproteasomes which contain three inducible catalytic b
subunits in place of the three standard catalytic subunits. The immunoproteasomes
can also be activated by association with an 11S regulator, which is composed of
two interferon-c-inducible subunits PA28a and PA28b.
synthesis by b1i, b2i and b5i subunits, respectively. As a result,
although these particles digest proteins at rates similar to those
for constitutive proteasomes, they generate a higher fraction of
peptides with the appropriate C-termini and length to serve in
antigen presentation. In immunoproteasomes, PA28 (11S) activa-
tor can replace the 19S complex [3] (Fig. 2).
3. Proteasomal activity during ageing
Homeostasis is a key feature of cellular lifespan. Maintenance of
cellular homeostasis influences the rate of ageing and its efficiency
is determined by the cooperation between protein stability and
resistance to stress, protein refolding, protein repair and proteoly-
sis of damaged proteins. Protein degradation is predominately cat-
alysed by the proteasome which is responsible for cell clearance of
abnormal or damaged proteins as well as for the regulated degra-
dation of short-lived proteins. Impaired proteasome function has
been tightly correlated to ageing both in vivo and in vitro. A number
of studies have shown that the proteasome can be activated by ge-
netic manipulations as well as by factors that affect either its con-
formation and stability or the expression of its subunits and the
rate of proteasome assembly. This ‘‘readjustment’’ has been shown
to have a great impact on retention of cellular homeostasis since it
promotes lifespan extension.
An age-related decrease in proteasome activity has been ob-
served in different tissues (including skin, muscle, heart, liver, kid-
ney, lung and eye lens). In all of these investigations, proteasome
activity was measured using fluorigenic peptide substrates and
caspase-like activity was found to be consistently depressed with
increasing age. Decreased activity could be due to reduced
amounts of proteasome. When the specific activity of 20S protea-
somes purified from different tissues was calculated, a loss of cas-
pase-like and chymotrypsin-like or trypsin-like activity was
 P. Löw / General and Comparative Endocrinology 172 (2011) 39–43
detected, supporting the link between intrinsic changes in 20S pro-
teasomes and increasing age. The concentration of ubiquitylated
proteins was also found to be increased in aged tissue and cells,
suggesting that the activity of 26S proteasomes could be affected
by ageing in addition to 20S proteasomes [8]. Earlier work has
attributed the observed decrease of proteasome function to the
accumulation of damaged proteins, such as lipofuscin, during age-
ing and senescence. Later it was revealed that the decreased func-
tion of proteasome in senescence is primarily due to the reduced
rates of proteasome biosynthesis and assembly. Moreover, it was
determined that replicative senescence is accompanied with
reduced levels of the b-type subunits, thus acting as the ‘‘rate-lim-
iting’’ subunits for efficient proteasome assembly [5].
In the mammalian muscle the proteasome-dependent proteo-
lytic pathway is sequentially regulated by amino acids during mat-
uration and ageing. The study of the respective role of insulin and
amino acids in the inhibition of proteolysis in the fed state sug-
gested a threshold of insulin induction below which proteasome-
dependent proteolysis may not be regulated. The lack of regulation
of skeletal muscle proteasome-dependent proteolysis in old rats is
mainly mediated by a resistance to amino acids [4].
As ageing is a progressive and irreversible (but not pathological)
phenomenon, a decline in proteasome activity may be regarded as
the natural answer to an age-related decrease in the rate of protein
synthesis, a process counterbalanced by protein degradation.
Therefore, it is no surprise that experimental inhibition of protea-
some activity in primary neuronal cells, for example, induces
impairments in protein synthesis, especially since many transcrip-
tion factors and some translation-initiation factors, as well as ribo-
some biogenesis, are regulated by proteasomal processing.
However, proteasome activity may also be necessary to remove
products of other processes that become imbalanced during age-
ing, such as the antioxidant response system. For example, a low-
ered capacity to eliminate oxidatively damaged proteins due to a
decrease in all three proteasome peptidase activities in eye lens
nuclei favours cataract formation in elderly individuals and, in
heart muscle, reduces tolerance of the aged heart to ischaemia/
reperfusion.
Structural alterations of proteasome subunits have been shown
to affect proteasome activity through changes of the 20S barrel
conformation. Initially, SDS and some fatty acids have been shown
to stimulate proteasome activities in vitro [9], whereas potassium
chloride has a negative effect [17] by favouring the open or the
closed conformation of the proteasome, respectively. Protea-
some-activating hydrophobic peptides have been shown to be
bound as modifiers at noncatalytic sites, thus mimicking the effect
of 11S complex by opening the a-gated pore [16]. The increased
activities promote cellular resistance to oxidants and confer exten-
sion of human fibroblasts lifespan [13].
4. Proteasome and neurodegeneration
A life-long steady decrease in proteasome activity is proposed
to be responsible for accumulation of abnormally folded proteins,
formation of inclusion bodies and development of neurodegenera-
tive diseases such as Alzheimer’s and Parkinson’s disease and Hun-
tington’s disease. Thus, age-related proteasomal dysfunction could
be regarded as a factor in these disease processes, which involve
the formation of plaques, filaments and aggregates. Once gener-
ated, these protein inclusions have been found to further inhibit
proteasome activity and thus amplify the formation of inclusion
bodies.
A major problem encountered by neurons during ageing that is
strongly linked to neurodegenerative disorders is the accumulation
of damaged proteins that form insoluble aggregates that accumu-
41
late in and/or outside of the cells. Damaged proteins are removed
by enzymatic degradation by cytosolic proteases, lysosomes and
the proteasome, and there is evidence that these three mecha-
nisms are altered in neurons during ageing [14,21]. In rats, protea-
some activity decreases with advancing age in the cerebral cortex,
hippocampus and spinal cord, but not in the cerebellum or brain-
stem [15]. Analyses of brain tissue samples suggest a much more
severe malfunction of the proteasomal system in Alzheimer’s dis-
ease [18] and Parkinson’s disease [20]. Several of the adverse con-
sequences of ageing on neuronal function and survival can be
mimicked by pharmacological inhibition of proteasomes [25] or
lysosomes [2]. In addition, increasing evidence suggests that im-
paired autophagy is important in neuronal dysfunction and death
in ageing and age-related disease [22].
In several neurodegenerative diseases, such as Huntington’s,
Alzheimer’s and Parkinson’s, autophagy tries to protect the cells
from the accumulation and aggregation of defective misfolded
cytosolic proteins caused by mutations in their genes, e.g. the poly-
glutamine-tract at the N-terminus of the Huntingtin protein in the
case of Huntington’s, b-amyloid precursor protein and the microtu-
bule-associated protein tau in Alzheimer’s, and a-synuclein in Par-
kinson’s disease. Under normal conditions, these proteins are
degraded by the ubiquitin–proteasome system, but in these neuro-
degenerative diseases this system becomes overwhelmed and
autophagy acts as a rescue system.
In rats, proteasome activity decreases with advancing age in the
cerebral cortex, hippocampus and spinal cord, but not in the cere-
bellum or brainstem. Analyses of brain tissue samples suggest a
much more severe malfunction of the proteasomal system in Alz-
heimer’s and Parkinson’s disease. Several of the adverse conse-
quences of ageing on neuronal function and survival can be
mimicked by pharmacological inhibition of proteasomes or lyso-
somes. In addition, increasing evidence suggests that impaired
autophagy is important in neuronal dysfunction and death in age-
ing and age-related disease. It has been shown that autophagy dis-
rupted during normal ageing can be restored by dietary restriction,
which is consistent with a possible role for impaired removal of
damaged organelles in neuropathologies of ageing. Proteins can
be altered by mutations, post-translational modifications, or by
intracellular or extracellular aggressors (oxidative stress, ultravio-
let radiation and toxic compounds) that often induce a change in
their conformation. The altered protein is usually recognised by
molecular chaperones, which are proteins that allow protein repair
or refolding. If the chaperones do not succeed in this repairing
activity, they send the altered protein to degradation—usually to
the ubiquitin–proteasome system.
However, if the activity of these systems is impaired, or the pro-
tein has already been organised into insoluble complex structures
(fibres or oligomers), macroautophagy is the only system that is
able to remove those toxic complexes. In conditions in which not
even macroautophagy can remove the altered proteins, these
aggregates usually trap other still-functional proteins inside them-
selves [19].
5. Insulin/IGF-1 signalling and the proteasome
The ubiquitin–proteasome pathway is a new partner for the
control of insulin signalling. The insulin-like growth factor type 1
(IGF-I) plays an important role in neuronal physiology. Reduced
IGF-I levels are observed during ageing and this decrease may be
important to age-related changes in the brain. IGF-I stimulates pro-
teasome activity, in a process mediated by the IGF-I receptor, PI3-
kinase/mTOR (mammalian target of rapamycin) signalling [7].
In frontal cortex the level of oxidised proteins is significantly
reduced in transgenic mice designed to overproduce IGF-I com-
42 P. Löw / General and Comparative Endocrinology 172 (2011) 39–43
pared with wild-type animals. The frontal cortex of IGF-I overpro-
ducing mice exhibited high chymotrypsin-like activity of the 20S
and 26S proteasomes. The proteasome can also be activated in re-
sponse to IGF-I in cell cultures. Kinetic studies revealed peak acti-
vation of the proteasome within 15 min following IGF-I
stimulation. The effects of IGF-I on proteasome were not observed
in R cells lacking the IGF-I receptor. Experiments using specific ki-
nase inhibitors suggested that activation of proteasome by IGF-I in-
volves phosphatidyl inositol 3-kinase and mammalian target of
rapamycin signalling. IGF-I also attenuated the increase in protein
carbonyl content induced by proteasome inhibition. Thus, appro-
priate levels of IGF-I may be important for the elimination of oxi-
dised proteins in the brain in a process mediated by activation of
the proteasome. IGF-I can increase proteasome activity through
the mTOR pathway in vitro and that IGF-I levels in the brain corre-
late with proteasome activity. This suggests that the neuroprotec-
tive effect of IGF-I may involve the clearance of deleterious
substances in the adult brain and favour the idea that maintaining
IGF-I levels in brain may be beneficial during ageing [7,10].
Insulin/IGF-1 signalling regulates ageing in worms, flies and
mammals. The insulin/IGF-1 receptor, through activating a cascade
of conserved kinases, inhibits the forkhead transcription factor,
FoxO. Longevity increases when FoxO becomes activated in re-
sponse to reduced insulin/IGF-1 signalling. These findings indicate
that IGF-I or insulin can reduce protein degradation rapidly by sup-
pressing autophagy via mTOR activation and independently Akt
suppressing FoxO transcription, which also inhibits proteasomal
degradation through the reduction of transcription of ubiquitin li-
gases atrogin-1 and MuRF1. Phosphorylation of FoxO in response
to insulin not only leads to its nuclear exclusion, but also to its
ubiquitin-mediated degradation through the 26S proteasome [27].
6. Ubiquitin–proteasomal degradation of IRS-1
While aberrations in the ubiquitin–proteasome pathway have
been implicated in certain malignancies and neurodegenerative
disorders, recent studies indicate a role for this system in the path-
ogenesis of diabetes and its complications. Inappropriate degrada-
tion of insulin signalling molecules such as insulin receptor
substrates (IRS-1 and IRS-2) has been demonstrated in experimen-
tal diabetes, mediated in part through the up-regulation of sup-
pressors of cytokine signalling (SOCS). It appears that altered
ubiquitin–proteasome system might be one of the molecular
mechanisms of insulin resistance in many pathological situations.
Drugs that modulate the SOCS action and/or proteasomal degrada-
tion of proteins could become novel agents for the treatment of
insulin resistance and Type 2 diabetes [1].
Insulin receptor substrate (IRS) proteins are important intracel-
lular molecules that mediate insulin receptor tyrosine kinase sig-
nalling. A decreased content of IRS proteins has been found in
insulin-resistant states in animals, humans and cultured cells un-
der various conditions. However, the molecular mechanism that
controls cellular levels of IRS proteins is unknown. Chronic insulin
treatment induces the degradation of IRS-1, but not IRS-2, protein
in cultured cells. The insulin-induced degradation of IRS-1 can be
prevented by pretreatment with lactacystin, a specific inhibitor
for proteasome degradation. These data demonstrate that insu-
lin-induced degradation of IRS-1 is mediated by the proteasome
degradation pathway.
Recent studies have revealed that IRS proteins are ubiquitylated
and subsequently degraded by the 26S proteasome during insulin
stimulation or during cellular stress [23,26]. In an elegant study,
White and his colleagues indicated that SOCS-1 and SOCS-3 (a fam-
ily of proteins called the suppressor of cytokine signalling, SOCS)
modulate insulin signalling by targeting IRS-1 and IRS-2, for
destruction by the proteasome [24]. Their work revealed two
important observations. First, SOCS-1 and SOCS-3 were shown to
have distinct binding sites for IRS-1 or IRS-2 and for elongin BC
ubiquitin ligase. Secondly, SOCS-mediated ubiquitylation of IRS-1
or IRS-2 is a necessary step for inhibition of insulin action in vari-
ous cell lines and mouse liver. This mechanism is consistent with
the function of SOCS-1 and SOCS-3 as adapter molecules linking
tyrosine-phosphorylated proteins to an elongin BC-based E3 ubiq-
uitin-ligase [12]. It appears that the ‘SOCS box’ acts as an adapter to
facilitate the ubiquitylation of signalling proteins and their subse-
quent targeting to the proteasome.
7. Conclusions
 Proteasome deficiency is both a cause and a consequence of
ageing, and contributes to the general decrease in protein integ-
rity and functionality with age.
 Longevity increases when FoxO becomes activated in response
to reduced insulin/IGF-1 signalling. IGF-I or insulin can reduce
protein degradation rapidly by suppressing FoxO transcription,
which also inhibits proteasomal degradation.
 Insulin-induced degradation of IRS-1 is mediated by the protea-
some degradation pathway.
 Damaged proteins are removed by the proteasome, and this is
altered in neurons during ageing. Age-associated neurodegener-
ative diseases such as Alzheimer’s disease and Parkinson’s dis-
ease are accompanied by an accumulation of damaged,
misfolded and biologically inactive proteins.
The importance of the ubiquitin–proteasome system for molec-
ular and cellular biology, as well as for medical sciences is increas-
ing. In regard to ageing of cells and tissues, the examples presented
in this review suggest that deregulation and changes of the protea-
some activity might have serious implications for ageing of organ-
isms as well as for ageing associated diseases. In any case, further
understanding of the influence of the ubiquitin–proteasome sys-
tem on the ageing process might help to identify targets for pre-
vention of deleterious loss of cell and tissue function and
pathogenesis of ageing related diseases.
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