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Mitochondrial Disorders in the Nervous System
Salvatore DiMauro1 and Eric A. Schon1,2
Departments of Neurology1 and Genetics and Development,2 Columbia University Medical Center, New York, NY 10032; email: email@example.com, firstname.lastname@example.org
Annu. Rev. Neurosci. 2008. 31:91–123 First published online as a Review in Advance on March 10, 2008 The Annual Review of Neuroscience is online at neuro.annualreviews.org This article’s doi: 10.1146/annurev.neuro.30.051606.094302 Copyright c 2008 by Annual Reviews. All rights reserved 0147-006X/08/0721-0091$20.00
mitochondrial DNA, maternal inheritance, oxidative stress, apoptosis, oxidative phosphorylation, aging
Mitochondrial diseases (encephalomyopathies) have traditionally been ascribed to defects of the respiratory chain, which has helped researchers explain their genetic and clinical complexity. However, other mitochondrial functions are greatly important for the nervous system, including protein importation, organellar dynamics, and programmed cell death. Defects in genes controlling these functions are attracting increasing attention as causes not only of neurological (and psychiatric) diseases but also of age-related neurodegenerative disorders. After discussing some pathogenic conundrums regarding the neurological manifestations of the respiratory chain defects, we review altered mitochondrial dynamics in the etiology of speciﬁc neurological diseases and in the physiopathology of more common neurodegenerative disorders.
INTRODUCTION . . . . . . . . . . . . . . . . . . DISEASES OF THE MITOCHONDRIAL RESPIRATORY CHAIN . . . . . . . . . . Disorders Caused by Mutations in mtDNA . . . . . . . . . . . . . . . . . . . . . . . . Disorders Caused by Mutations in nDNA . . . . . . . . . . . . . . . . . . . . . . . . . DISEASES CAUSED BY IMPAIRED MITOCHONDRIAL PROTEIN IMPORT . . . . . . . . . . . . . . . . . . . . . . . . . DISEASES CAUSED BY ABERRANT MITOCHONDRIAL DYNAMICS . . . . . . . . . . . . . . . . . . . . . . AGING AND LATE-ONSET NEURODEGENERATIVE DISORDERS . . . . . . . . . . . . . . . . . . . . . Mitochondria and Neurodegeneration . . . . . . . . . . . . . . . . Neurodegenerative Diseases Caused by Mutations in Nuclear-Encoded Proteins Targeted to Mitochondria . . . . . . . . . . . . . . . . . . . MITOCHONDRIAL PSYCHIATRY . . . . . . . . . . . . . . . . . . . . CONCLUSIONS . . . . . . . . . . . . . . . . . . . . 92
93 93 97
108 112 113
Mitochondrial dysfunction plays a crucial role in neurology. This notion became apparent three decades ago when pediatric neurologists
Table 1 Mitochondrial respiratory chain disease targets Mutations in nDNA R.C. subunits Complex I, II, III Ancillary proteins Complex I, III, IV, V; CoQ Intergenomic communication Multiple mtDNA deletions Depletion of mtDNA Translation of mt-mRNAs Mitochondrial lipids
Mutations in mtDNA R.C. subunits Protein synthesis genes Rearrangements tRNAs rRNAs
coined the term mitochondrial encephalomyopathies to call attention to the frequent occurrence of brain disease in children with mitochondrial alterations in their muscle biopsies (Shapira et al. 1977). The selective vulnerability of skeletal muscle and of the nervous system was conﬁrmed in 1988, when the ﬁrst pathogenic mutations in the mitochondrion’s own DNA (mtDNA) were discovered (Holt et al. 1988, Wallace et al. 1988). These discoveries heralded the era of mitochondrial genetics and led to the recognition of a multitude of mtDNA-related disorders, mostly maternally inherited and mostly manifesting as encephalomyopathies (DiMauro & Davidzon 2005, DiMauro & Schon 2003). Because mtDNA encodes only 13 proteins, all of them subunits of the mitochondrial respiratory chain—the business end in terms of ATP production—another notion became widely accepted: The term mitochondrial encephalomyopathies was reserved for defects of the respiratory chain. Even within these boundaries, the classiﬁcation of the mitochondrial encephalomyopathies soon became quite cumbersome, including two ﬂavors of primary mtDNA mutations (i.e., the impairment of global mitochondrial protein synthesis and of the translation of speciﬁc respiratory chain subunits) and a much larger menu of Mendelian disorders (Table 1). Also, genetic errors in other fundamental mitochondrial functions that do not affect the respiratory chain directly have major deleterious effects on the nervous system, including impaired importation of mitochondrial proteins and defects of mitochondrial dynamics, such as motility, ﬁssion, fusion, and distribution. Another topic of current interest is the role of progressive mitochondrial dysfunction in normal aging and in the pathogenesis of lateonset neurodegenerative disorders. In this review, we discuss ﬁrst the nervous system disorders caused by mitochondrial respiratory chain defects, emphasizing how their pathogenesis is still largely terra incognita. We then consider the burgeoning new group of disorders attributed to defects of mitochondrial
Annu. Rev. Neurosci. 2008.31:91-123. Downloaded from www.annualreviews.org by Columbia University on 01/19/12. For personal use only.
Annu. Rev. Neurosci. 2008.31:91-123. Downloaded from www.annualreviews.org by Columbia University on 01/19/12. For personal use only.
dynamics. Last, we review the neurodegenerative disorders in which mitochondrial dysfunction is either primary or seems to be at least involved in pathogenesis. We do not discuss mitochondrial metabolic pathway defects other than the respiratory chain, such as pyruvate dehydrogenase complex (PDHC) deﬁciency or βoxidation defects, although the nervous system is frequently affected in those disorders, too.
DISEASES OF THE MITOCHONDRIAL RESPIRATORY CHAIN
These diseases can be caused by mutations in mtDNA (sporadic or maternally inherited traits) or by mutations in nuclear DNA (nDNA; Mendelian diseases).
inorganic phosphate (Pi) to ATP in a tripartite series of catalytic reactions [three sets of α/β dimeric subunits alter their conformations via a rotating “cam” that connects Fo to F1 so as to bind ADP +Pi ﬁrst, then to convert ADP and Pi to form ATP, and ﬁnally to release the ATP into the matrix, where it is exported from the organelle into the cytoplasm via the adenine nucleotide translocator (ANT)]. At this point, a brief reminder of the rules of mitochondrial genetics is “de rigueur.” 1. Heteroplasmy and threshold effect. Each cell contains hundreds or thousands of mtDNA copies, which, at cell division, distribute randomly among daughter cells. In normal tissues, all mtDNA molecules are identical (homoplasmy). Deleterious mutations of mtDNA usually affect some but not all mtDNAs (heteroplasmy), and the clinical expression of a pathogenic mtDNA mutation is determined largely by the relative proportions of normal and mutant genomes in different tissues. A minimum critical mutation load (typically above 80%–90%) is required to cause mitochondrial dysfunction in a particular organ or tissue and mitochondrial disease in an individual: This is the threshold effect. 2. Mitotic segregation. At cell division, the proportion of mutant mtDNAs in daughter cells may shift and the phenotype may change accordingly. This phenomenon, called mitotic segregation, explains how the clinical phenotype in patients with mtDNA-related disorders may change as patients grow older. 3. Maternal inheritance. At fertilization, all mtDNA derives from the oocyte. Therefore, the mode of transmission of mtDNA and of mtDNA point mutations (single deletions of mtDNA are usually sporadic events) differs from Mendelian inheritance. A mother carrying a mtDNA point mutation will pass it on to all her children (males and females), but only the daughters will transmit it to their progeny. Thus, a disease expressed in both sexes
mtDNA: mitochondrial DNA PDHC: pyruvate dehydrogenase complex nDNA: nuclear DNA
Disorders Caused by Mutations in mtDNA
Human mtDNA (Figure 1) is a 16.6-kb circular, double-stranded molecule, which contains 37 genes: 2 rRNA genes, 22 tRNA genes, and 13 structural genes encoding subunits of the mitochondrial respiratory chain (Anderson et al. 1981). Reducing equivalents produced in the Krebs cycle and in the ß-oxidation “spiral” are passed along a series of protein complexes embedded in the inner mitochondrial membrane (the electron transport chain), which consists of four multimeric complexes (I, II, III, and IV) plus two small electron carriers, coenzyme Q (or ubiquinone) and cytochrome c (Figure 2). The energy generated by the reactions of the electron transport chain is used to pump protons from the mitochondrial matrix into the intermembrane space (IMS) located between the inner and outer mitochondrial membranes. This process creates an electrochemical proton gradient, which is utilized by complex V (or ATP synthase), a tiny rotary machine that generates ATP as protons ﬂow back into the matrix through its membraneembedded F0 portion, the rotor of the turbine. The motor’s stator (called the F1 portion) protrudes into the matrix and converts ADP and
www.annualreviews.org • Mitochondrial Disorders in the Nervous System
org) that affect the nervous system in particular are indicated (colors correspond to those of the affected genes). LHON D Epilepsy ND4L R K G COX II Alpers-like A8 MERRF A6 NARP MILS FBSN COX III LS ND3 LS Figure 1 The human mitochondrial genome. and 22 tRNAs (1-letter amino acid nomenclature) are shown. cytochrome b (Cyt b). 2008. follow the Supplemental Material link from the Annual Reviews home page at http://www.org by Columbia University on 01/19/12. The mtDNA-encoded gene products for the 12S and 16S ribosomal RNAs. Downloaded from www. Rev. Some pathogenic mutations (for expanded versions of all the key terms in this article.annualreviews. see Supplemental Term List. Supplemental Material but with no evidence of paternal transmission is strongly suggestive of an mtDNA point mutation.HSP 12 S V F OH D-Loop T Parkinsonism Cyt b 16 S Annu. especially if myopathies are considered—as they should—the domain of peripheral neurology.and light-strand transcription (HSP and LSP).annualreviews. For personal use only. About 200 mtDNA point mutations and innumerable single large-scale (kilobase-sized) 94 DiMauro partial deletions have been associated with human diseases. and ATP synthase (A). most of which affect the central and peripheral nervous system.and light-strand replication (OH and OL ) and the promoters of heavy. P LSP MELAS L E LS. This concept · Schon . as are the origins of heavy. Neurosci. LHON Dystonia ND6 LHON Dystonia ND1 I M Q ND5 LS ND2 W A N C Y OL KSS L S H MELAS MND Epilepsy COX I S ND4 LS. the subunits of NADH-coenzyme Q oxidoreductase (ND). cytochrome c oxidase (COX).31:91-123.
These are not described here in any more detail because the features can be found in textbook reviews (Hays et al. in more detail. III. and are pumped back to the matrix through complex V to produce ATP. 2006. 2006a). Protons are pumped from the matrix to the intermembrane space through complexes I. which highlights the typical clinical features of the ﬁve most common mtDNA-related syndromes of neurological interest. The human mitochondrial genome is saturated with mutations. Coenzyme Q and cytochrome c are electron (e− ) transfer carriers.org by Columbia University on 01/19/12. is illustrated in Figure 1 and. and yet the severity 95 Supplemental Material www.org • Mitochondrial Disorders in the Nervous System . Does this mean that we are scraping the bottom of the barrel as far as our understanding of mtDNA-related diseases is concerned? Not by a long stretch. some mutations are homoplasmic. the pace at which new pathogenic mutations are discovered has slackened in recent years. Rev.annualreviews. Neurosci. Genes in bold encode RC subunits. Matrix IMM IMS Succinate ND1 ND2 ND3 ND6 ND4 ND5 ND4L Fumarate O2 e– e– CoQ COX I COX II COX III ADP H 2O A8 A6 ATP e– Cyt b e– Complex III 1 10 Cyt c e– Complex I Complex II 0 4 Complex IV 3 10 Complex V 2 ~16 mtDNA-encoded subunits 7 nDNA-encoded subunits ~39 Mutated genes NDUFA1 NDUFS1 NDUFS2 NDUFS3 NDUFS4 NDUFS6 NDUFS7 NDUFS8 NDUFV1 NDUFV2 NDUFA12L SDHA SDHB SDHC SDHD APTX COQ2 PDSS1 PDSS2 BCS1L UQCRB COX10 COX15 LRPPRC SCO1 SCO2 SURF1 ATPAF2 Diseases Leigh syndrome Leukodystrophy Leigh syndrome Encephalomyopathy Nephrosis Leigh syndrome Encephalomyopathy Leigh syndrome Cardioencephalomyopathy Leukodystrophy/ tubulopathy Fatal infantile encephalomyopathy Figure 2 The mitochondrial respiratory chain (RC). in Table 2. Hirano et al.31:91-123. and several questions still await answers in the ﬁeld of mitochondrial genetics. Diseases (see Supplemental Term List) caused by mutations in mtDNA (above the RC) and in nDNA (below the RC) are listed according to the correspondingly affected RC complex.Diseases LHON MELAS LHON + dystonia Leigh syndrome Encephalomyopathy ALS–like syndrome Encephalomyopathy NARP MILS FBSN Mutated genes ND1 – ND6 Cyt b COX I – COX III ATPase 6 Annu. Downloaded from www. Although. and IV. showing nDNA-encoded subunits (blue) and mtDNA-encoded subunits (colors corresponding to the genes in the map in Figure 1). 2008. novel mutations are still being reported.annualreviews. For personal use only. For example. understandably. those in plain text encode ancillary or assembly proteins. whereas most pathogenic mtDNA mutations are heteroplasmic and clinical severity is usually related to mutation load.
Rev. In fact. A related question concerns the functional signiﬁcance of mtDNA haplotypes. Neurosci. Although clinical overlap does occur in mtDNA-related diseases. In the migration out of Africa. thus inﬂuencing the overall physiology of individuals and predisposing them to—or protecting them from—certain diseases (Carelli et al. Downloaded from www. If. 2006). of the syndromes they cause differs in different families or even in members of the same family.org by Columbia University on 01/19/12. 1999). as conventional wisdom dictates. 2008.” resulting in several haplotypes characteristic of different ethnic groups (Wallace et al. Clearly. human beings have accumulated distinctive variations on the mtDNA of the ancestral “mitochondrial Eve. it would be logical to expect a clinical swamp of illdeﬁned and overlapping symptoms and signs. much work remains to be done to deﬁne better both the pathogenic role of homoplasmic mutations 96 DiMauro and the modulatory role of haplotypes in health and disease. A major problem in mtDNA-related neurological diseases is our woeful ignorance about genotype-phenotype correlations. both large-scale mtDNA rearrangements and point mutations in rRNA or tRNA genes impair mitochondrial protein synthesis and ATP production. For personal use only. it is fair to say that · Schon .31:91-123. it is surprising that mtDNA mutations should cause different syndromes in the ﬁrst place. as originally predicted by the “lumpers” (Rowland 1994).annualreviews. Different mtDNA haplotypes may modulate oxidative phosphorylation.Table 2 TISSUE Clinical features in diseases associated with mtDNA mutations Δ-mtDNA SYMPTOM/SIGN KSS tRNA ATPase6 MERRF MELAS NARP MILS Annu.
not explanations. MERRF. the 3243-MELAS mutation is abundant in the walls of cerebral arterioles (Betts et al. in that most mutations result in well-deﬁned syndromes. MELAS. the mtDNA has lost more than 99% of its original genes and most Immunohistochemistry to detect the mtDNA-encoded COX II subunit of complex IV (left panels) and the nDNA-encoded FeS subunit of complex III (right panels) in brain structures in three mtDNA-related diseases. and MELAS. Direct evidence of the accumulation of -mtDNA in the choroid plexus of KSS patients was provided by Tanji et al. However. H) and a MERRF patient (I. However these are mere associations.org by Columbia University on 01/19/12. Neurosci. COX II FES Control Annu. immunohistochemical evidence suggests that the mtDNA deletion ( -mtDNA) of KSS abounds in the choroid plexus (Tanji et al. MERRF. Olivary nucleus from a control (G.31:91-123. Choroid plexus from a control (A. 2001) (Figure 3g–j ). Rev. diabetes is a frequent manifestation of the T14709C mutation in tRNAGlu . LHON. and SNHL. Consistent with clinical symptoms and laboratory data. these data fail to explain what directs each mutation to a particular area of the brain. That mutations in different tRNA genes may have different mechanisms of action is suggested by the apparently selective tissue vulnerability associated with mutations in some tRNAs: For example. Sub-pial arterioles from a MELAS patient (E. To explain the distinctive brain symptoms in patients with KSS. DAD. Courtesy of Drs.org • Mitochondrial Disorders in the Nervous System . B) and a KSS patient (C. how the mutation correlates with the clinical syndrome. (2000) using in situ hybridization (Figure 4).the “splitters” won the day.annualreviews. and multiple lipomas have been reported only in patients with mutations in tRNALys . and the 8344-MERRF mutation is abundant in the olivary nucleus of the cerebellum (Tanji et al. NARP/MILS. D). Columbia University Medical Center. a b KSS c d MELAS e f Control g h MERRF i Figure 3 j Disorders Caused by Mutations in nDNA During the many millennia of symbiotic relation with the nDNA. 2000) (Figure 3a–d ). F). the different mutations have been “mapped” indirectly through immunohistochemical techniques. 97 www. For personal use only. It is fair to conclude that the pathogenesis of mtDNA-related disorders is still largely unexplained. Eduardo Bonilla and Kurenai Tanji. cardiomyopathy is often associated with mutations in tRNAIle . including mutations associated with KSS/PEO. or why the syndromes differ from each other. J).annualreviews. 2006) (Figure 3e–f ). Downloaded from www. 2008.
Deletion b Probe 1 Probe 2 Normal KSS Figure 4 In-situ hybridization to detect mtDNAs in the choroid plexus from a KSS patient. and it now depends on nuclear factors for all its basic functions. and V (ATPase 6). For personal use only. It is more difﬁcult to explain why severe COX deﬁciency with recessive mutations in assembly proteins (for example SCO2) is still compatible with life. Courtesy of Drs. M AR AR M M M AR XR. which is located at the C-terminus of the protein and still allows for some residual complex III activity. 2008. (a) Map of wt. the series/parallel hypothesis has been undercut by the ﬁnding of a homozygous frameshift mutation in the ubiquinone-binding subunit of complex III UQCRB (Haut et al. M.annualreviews. including replication. probe 2 (blue) detects only wt-mtDNA. IV. · Schon . X. of its autonomy. there is a much stronger signal in the patient with probe 1 than with probe 2 (lower panels). IV (COX I.org by Columbia University on 01/19/12. synthesis of most respiratory chain subunits. albeit a very abbreviated life. Downloaded from www. whereas complexes III. II. or III).and -mtDNAs. However.and -mtDNAs from the patient showing the two probes: Probe 1 (red ) detects both wt. These mutations (direct hits) have been found predominantly in the ﬁrst two complexes of the respiratory chain. The hallmark neuropathological lesions of this devastating neurodegenerative disorder of infancy or early Table 3 Defect Complex I Complex II Complex IV Complex V tRNALeu(UUR) tRNALys CoQ10 PDHC Causes of Leigh syndromea Transmission AR. allowing for some residual electron transport even when one complex is out of commission. translation. X-linked. and V are in series (Figure 2). This is why the Mendelian defects of the respiratory chain 98 DiMauro a Abbreviations: AR. and assembly of respiratory chain complexes. autosomal recessive. Rev. Columbia University Medical Center. suggesting that deleterious mutations in the terminal complexes are either rare or incompatible with life. Although direct hits do occur in the mtDNA-encoded subunits of complexes III (cytochrome b). and for the synthesis of the phospholipids that constitute the inner mitochondrial membrane (IMM). maternal. indicating a massive accumulation of -mtDNAs. Eduardo Bonilla and Kurenai Tanji. AR Frequency +++ + +++ ++ + + + +++ wt-mtDNA ∆-mtDNA Annu. Mutations in genes encoding respiratory chain subunits. 2003). Most mutations in nDNA-encoded complex I or in complex II subunits cause Leigh syndrome (LS) (Table 3).31:91-123. the heteroplasmic nature of these mutations may permit some residual activity. One explanation suggests that complexes I and II are in parallel. Neurosci.a Probe 1 Probe 2 can be divided into at least four subgroups (Table 1). (b) As opposed to the uniform signal with both probes in the control (upper panels).
rarely.org • Mitochondrial Disorders in the Nervous System 99 .31:91-123. than are women. and yet the complex I deﬁciency is not particularly severe. another COX-deﬁcient form of LS associated with liver diseases and KSS: Kearns-Sayre syndrome PEO: progressive external ophthalmoplegia MERRF: Myoclonus epilepsy ragged-red ﬁbers MELAS: mitochondrial encephalomyopathy. led to the identiﬁcation of LRPPRC. 1998. Integrative genomics. whereas some LHON mutations are heteroplasmic (as in most mitochondrial diseases). and yet the pathology is conﬁned. most are homoplasmic. This concept is supported by the observation that LS is also caused by mtDNA mutations when they are sufﬁciently abundant (MILS. on the whole. Also. First. the blindness usually does not occur until the patient is older than age 20. even though the mutation is often homoplasmic. (b) T2-weighted MRI showing abnormal bilateral symmetrical hyperintense signals in the lenticular nuclei (arrowheads). Third. the blindness is partially reversible. although LHON is maternally inherited. which led to the identiﬁcation of the most common gene responsible for COXdeﬁcient LS. Fourth. most do not. and strokelike episodes NARP: Neuropathy. the gene responsible for LS-FrenchCanadian type (LSFC). implying an X-linked modiﬁer effect (Hudson et al. neuronal loss. retinitis pigmentosa LS: Leigh syndrome MILS: Maternally inherited Leigh syndrome LHON: Leber hereditary optic neuropathy www. to the retinal ganglion cells (Carelli et al. on the basis of information derived from DNA. and especially COX deﬁciency.annualreviews. and demyelination in the basal ganglia.annualreviews. Annu.a b Figure 5 Typical brain lesions in Leigh syndrome. vascular proliferation. SURF1 (Tiranti et al. that is. Rev. Mutations in genes encoding ancillary proteins.org by Columbia University on 01/19/12. but rather cause Leber hereditary optic neuropathy (LHON). childhood [bilaterally symmetrical foci of cystic cavitation (Figure 5). lactic acidosis. For personal use only. and proteomics studies. together with their prosthetic groups. Downloaded from www. 2007. 2007). 2005). all pathogenic LHON mutations are in complex I genes. and then each eye is affected sequentially within months. Neurosci. came from yeast genetics because most genes needed for COX assembly in yeast have human homologues. 2003. 1998). Another shortcut to ﬁnding mutant genes without sequencing multiple candidate COX-assembly genes was the search for complementation in COX-deﬁcient cultured cells from patients via monochromosomal hybrid fusion or microcell-mediated chromosome transfer. brainstem. men are affected far more frequently.and mtDNA-encoded subunits. (a) Coronal section showing bilateral symmetrical cavitating lesions in the basal ganglia (arrows). mRNA. mutations in proteins that are not part of any complex but are needed to synthesize and direct the proper assembly of the various nDNA. 2008. Tatuch et al. Second. a maternally inherited optic atrophy that causes blindness in young adults with challenging contradictions. and posterior columns of the spinal cord] probably reﬂect the stereotypical ravages caused by defective oxidative metabolism on the developing nervous system. Zhu et al. 1992). ataxia. and more severely. This group of disorders is caused by indirect hits. Table 2) or severe enough to impair oxidative phosphorylation early in life (Kirby et al. Although some mutations in mtDNA complex I genes cause LS. Important clues to the molecular etiology of these disorders. Sarzi et al.
Downloaded from www. 2006). 2005). 2003. Mollet et al. 2006. Rev. 100 DiMauro · Schon .org by Columbia University on 01/19/12. Because at least nine enzymes are needed to synthesize CoQ10 . 2007.2L). Mutations in two CoQ10 biosynthetic enzymes (in the PDSS1 and PDSS2 subunits of of COQ1. Knowledge of the molecular defects in these fatal infantile neurological disorders offers young parents who have lost one child the option of prenatal diagnosis. Morin et al. 2007).annualreviews. Quinzii et al. in a child with severe cavitating leukoencephalopathy (Ogilvie et al. For personal use only. 2008. A bioinformatics approach was also used to identify the ﬁrst mutant assembly gene responsible for complex I deﬁciency. mutations in the other seven enzymes will probably also be associated with encephalomyopathic syndromes (DiMauro et al. Neurosci.31:91-123. Primary coenzyme Q10 (CoQ10 ) deﬁciency encompasses disorders caused by blocks in the biosynthetic pathway of this small ubiquinone carrier. Several syndromes have also been associated with a presumed secondary CoQ10 deﬁciency. NDUFA12L (formerly called B17.Annu. and in COQ2) have been identiﬁed in infants or children with encephalomyopathy (one of them had ´ LS) and nephrotic syndrome (Lopez et al. CoQ10 transfers electrons from complexes I and II to complex III and receives electrons from the β-oxidation pathway via the electron transfer ﬂavoprotein dehydrogenase (ETF-DH) (Figure 6). 1993). prevalent in the Saguenay-Lac Saint-Jean region of Quebec (Mootha et al. These include autosomal recessive Pyruvate OMM IMS IMM Matrix Fatty acids PDHC β-oxidation Acetyl-CoA Krebs cycle ETF ETF-DH SDH ND1 ND2 ND3 ND6 ND4 ND5 ND4L Cyt b CoQ Cyt c COX I COX II COX III A8 A6 Figure 6 Schematic of mitochondrial intermediate metabolism showing the relationships between pyruvate and fatty acid metabolism and ATP synthesis. Note that the electron-transfer ﬂavoprotein (ETF) delivers electrons from the β-oxidation pathway to CoQ10 via the ETF-dehydrogenase (ETF-DH).
or by defective translation of mtDNA-encoded respiratory chain components. The resulting Mendelian disorders are characterized by qualitative (multiple deletions) or quantitative (depletion) alterations of mtDNA. all involved in the homeostasis of the mitochondrial nucleotide pools. the pool of available candidate genes has yet to be exhausted (DiMauro & Hirano 2005). POLG2 mtDNA ADP TP Thymine ANT1 dNDP dNTP ATP rNDP RRM2B Figure 7 Schematic of nucleotide metabolism for mtDNA synthesis and replication. Defects of intergenomic communication. and a predominantly myopathic form of glutaric aciduria type II (GAII) caused by mutations in the electron transfer ﬂavoprotein dehydrogenase gene (ETFDH) (Gempel et al. have been associated with PEO and multiple mtDNA dA dG dA DGUOK dG dAMP dGMP dADP dGDP dATP dGTP ETN1 dC dT dC dT AK2. most of these disorders are caused by alterations in the pools of nucleotides required to synthesize mtDNA.org • Mitochondrial Disorders in the Nervous System 101 . knowledge of CoQ10 deﬁciency syndromes is important for physicians because most patients improve with CoQ10 supplementation. the ear (sensorineural hearing loss). or in enzymes associated with mtDNA replication itself (Spinazzola & Zeviani 2005) (Figure 7).31:91-123.org by Columbia University on 01/19/12. but rather are the result of garbled messages from the nuclear OMM IMS IMM Multiple mtDNA deletions. Neurosci. Aside from its scientiﬁc importance. The other respiratory complexes obviously also require assembly. and translation. including peripheral nerves (sensorimotor neuropathy). the brain (ataxia. which controls mtDNA replication. Genes in bold have been associated with diseases characterized by multiple mtDNA deletions and/or with mtDNA depletion. and mutations in assembly factor BCS1L for complex III (Visapaa et al. proximal weakness). 2005). which are almost invariably associated with extramuscular system involvement. www. From the clinical point of view. psychosis). 2008. 2004) have also been found. and the eye (cataracts). the syndrome of ataxia and oculomotor apraxia (AOA1) caused by mutations in the aprataxin gene (APTX) (Quinzii et al. maintenance.annualreviews. POLG. SUCLG1 dCDP dTDP dCTP dTTP PEO1. Rev.Annu. UCK TK2 NT5M dCMP dTMP NME4. Mutations in several genes.annualreviews. The alterations of mtDNA of some disorders are not caused by primary mutations of the mitochondrial genome. ptosis. cerebellar ataxia of unknown etiology in children. For personal use only. 2007) (Figure 6). dementia. NME6 SUCLA2. Clearly. Downloaded from www. Of note. multiple mtDNA deletion syndromes share the cardinal features of ocular and limb myopathy (PEO. genome. 2002) and ATPAF2 for complex V (De Meirleir et al.
e. which encodes the adenosine nucleoside translocator. encoding the β subunit of the mitochondrial matrix enzyme succinyl-CoA synthetase (Elpeleg et al. and gastrointestinal symptoms (DiMauro et al. which encodes the enzyme deoxyguanosine kinase (dGK). as do platelet infusions. parkinsonism. mutations in the dimeric accessory subunit POLG2. which encodes the cytosolic enzyme thymidine phosphorylase (TP). Both forms of inheritance are encountered in adults with PEO and multiple mtDNA deletions: Clinical manifestations include ataxia. which encodes the mitochondrial polymerase γ catalytic subunit. We have seen how some mutations in POLG predominantly cause mtDNA depletion and result in a severe infantile hepatocerebral disorder (Alpers syndrome). and (b) a purely or predominantly myopathic syndrome associated with mutations in TK2.31:91-123. which has a polymerase (i. This clinical heterogeneity can.e. 2005). POLG. peripheral neuropathy. not all cases of mtDNA depletion are explained by mutations in these four genes. an obvious therapeutic approach. clinical efﬁcacy remains to be ﬁrmly documented (Hirano et al. has only transient effects. Depletion of mtDNA. a severe hepatocerebral disease associated with DiMauro Annu. 2006b). For reasons that are not completely clear. can also cause autosomal dominant PEO (Longley et al. PEO1. which is responsible for processive DNA synthesis and tight binding of the POLG complex to DNA. be attributed to the site of the mutation in the catalytic subunit. which encodes a helicase called Twinkle. Two such toxic intermediates. some children with hepatocerebral syndrome harbored pathogenic mutations in a gene on chromosome 2. For personal use only. For example. Although the patient has improved subjectively 18 months after the procedure. caused by mutation either in POLG or in DGUOK. MPV17. causing not only multiple deletions. leukoencephalopathy. encoding the cytosolic p53-inducible ribonucleotide reductase small subunit (p53R2) (Bourdon et al. whereas adults with PEO tend to have mutations solely in the polymerase domain. and POLG2.annualreviews. 2006a). accumulate massively in the blood of MNGIE patients. and with mutations in RRM2B. This muscle paradox suggests that TP deﬁciency acts through toxic intermediates. neuropathy. myoclonus epilepsy. although muscle expresses little TP (Hirano et al.. 2005). replicating) domain and an exonuclease (i. However. In fact. which encodes the mitochondrial form of the enzyme thymidine kinase. mutations in other proteins controlling the mitochondrial nucleotide pool also cause mtDNA depletion. 2007). with mutations in SUCLA2. proofreading) domain joined by a “linker” region: Most patients with Alpers syndrome have at least one mutation in the linker region and another in the polymerase domain.org by Columbia University on 01/19/12. and intestinal dysmotility leading to cachexia and early death. ECGF1. psychiatric disorders. Disorders associated with mutations in POLG are inherited as either autosomalrecessive or autosomal-dominant traits. at least in part. Neurosci. but allogeneic bone marrow transplantation in one patient restored TP activity in buffy coat cells and normalized blood levels of thymidine and deoxyuridine.. the degree of depletion varies in different tissues. but two major syndromes have emerged: (a) hepatocerebral syndrome. mtDNA depletion and extreme vulnerability to valproate administration (Naviaux & Nguyen 2004). Autosomal recessive inheritance of mutations in POLG is the rule in children with Alpers syndrome. 1999) and characterized clinically by PEO. Downloaded from www. an autosomal recessive multisystem disease of young adults caused by mutations in TP (Nishino et al. To complicate matters further. The ﬁrst is MNGIE (mitochondrial neurogastrointestinal encephalomyopathy). These include ANT1. and not all mutated genes are involved in nucleotide pool homeostasis. Rev. The lack of TP activity damages mtDNA synthesis. but also depletion and point mutations. 2008. 2006). which encodes an 102 · Schon . thymidine and deoxyuridine. Hemodialysis. which encodes the dimeric accessory subunit of POLG (Spinazzola & Zeviani 2005). which are evident in skeletal muscle.MNGIE: mitochondrial neurogastrointestinal encephalomyopathy deletions. Two of these disorders are of special interest to neurologists.
genetic abnormalities of cardiolipin could impair respiratory chain function in humans. the third. IMM protein of unknown function (Spinazzola et al. For personal use only. Valente et al. 2004). encephalopathy. Rev. all encoded by nDNA. TUFM. Defects in mtDNA translation result in severe combined respiratory chain complex defects. RNA modiﬁcation enzymes. intact respiratory chain function is essential for cardiolipin biosynthesis (Gohil et al. and imported into the organelle. the second. 2006). 2005b) and interacts directly with COX (Sedlak et al. Downloaded from www. Defects of mtDNA translation. have been identiﬁed in three families (Bykhovskaya et al. 2006). and caused by mutations in the gene encoding a phospholipid acyltransferase called tafazzin (TAZ) (Schlame & Ren 2006). but this number will certainly increase in the years to come. Mutations affecting the lipid milieu of the respiratory chain. The best candidate for this role is Barth syndrome. 2004. encodes one of four ribosomal elongation factors (Coenen et al. IMM. and it is important to think of this pathogenic mechanism in infants or children with hepatocerebral syndrome. We can now provide sound genetic counseling to the Navajo population in the hopes of eradicating this dreadful disease. IMS. and mutations in TAZ alter the concentration and composition of cardiolipin. 2006).org • Mitochondrial Disorders in the Nervous System . The complexes of the respiratory chain are embedded in the lipid milieu of the IMM. Fernandez-Vizarra et al. MRPS16. leading to altered mitochondrial architecture and function. or cardiomyopathy and otherwise unexplained multiple respiratory chain defects. and growth retardation. Neurosci. Cardiolipin does not have merely a scaffolding function. 2008.annualreviews. 2007). DISEASES CAUSED BY IMPAIRED MITOCHONDRIAL PROTEIN IMPORT Of the 1300+ proteins found in mammalian mitochondria (Schon 2007). encodes the mitochondrial ribosomal protein subunit 16 (Miller et al. GFM1. A different syndrome is caused by defective pseudouridylation of mitochondrial tRNAs and is characterized by myopathy. Faithful translation of the 13 mtDNA-encoded subunits of the respiratory chain requires not only intact mtDNA. probably because of some as-yet-unknown genetic modiﬁer. infantile cavitating leukoencephalopathy. 2006). encodes the elongation factor Tu (Valente et al. synthesized in the cytoplasm.annualreviews. The ﬁrst gene. 2004). Thus far. lactic acidosis. 2006). 2004. an acidic phospholipid. and sideroblastic anemia (MLASA): Mutations in this gene. Mitochondrial import is a complex process. Some TAZ mutations cause mislocalization of cardiolipin from the outer mitochondrial membrane (OMM) and IMM to the mitochondrial matrix (Claypool et al. The disease is called Navajo neurohepatopathy (NNH) to stress that neuropathy rather than encephalopathy accompanies the liver dysfunction in this condition.Annu. 2007). but also participates in the formation of supercomplexes (stoichiometric assemblies of individual respiratory chain complexes into functional units) (Zhang et al. All others are encoded by nDNA genes. and termination factors. with different pathways for protein targeting and sorting to each of the four mitochondrial compartments (OMM. whose major component is cardiolipin. and initiation. PUS1. conversely. but also ribosomal proteins.31:91-123. and the matrix enveloped 103 www. which encodes the mitochondrial enzyme pseudouridine synthase 1. TSFM. 2006). a trustworthy polymerase. cardiomyopathy. elongation. Tafazzin promotes structural uniformity and molecular symmetry among cardiolipin molecular species. encodes the mitochondrial elongation factor EFTs (Smeitink et al. only 13 are encoded by mtDNA. and the availability of nucleotide building blocks.org by Columbia University on 01/19/12. Therefore. investigators have described mutations in four genes. and the fourth gene. an X-linked recessive disorder characterized by mitochondrial myopathy. The importance of this gene was bolstered by the ﬁnding that the same homozygous mutation encountered in a southern Italian family is the cause of a disease endemic in the Navajo population of the American southwest (Karadimas et al.
The need for mitochondrial motility is nowhere more evident than in motor neurons of the anterior horn cells. such as methylmalonic acidemia (Ledley et al. Upon a signal to divide. Although a few mutations in leader peptides have been associated with speciﬁc enzyme defects. Once inside the mitochondrion. where they often form tubular networks that may favor the delivery of organelles to areas of high energy demand (Bossy-Wetzel et al. 2006). Mdv1p and Caf4p. 2004) (Figure 8). In yeast. and Caf4p (carbon catabolite repression-associated factor). apparently through the action of yet another protein called Mgm1p (mitochondrial genome maintenance protein 1). One of these is an X-linked recessive deafness-dystonia syndrome (Mohr-Tranebjaerg syndrome) caused by mutations in the gene (TIMM8A) encoding the deafness/dystonia protein (DDP). the mitochondrial targeting signal (MTS. 2008. Another is an autosomal dominant form of hereditary spastic paraplegia (HSP type 13. a presequence translocation-associated motor (PAM). SPG13) caused by mutations in the import chaperonin HSP60 (Hansen et al. Remembering their bacterial origin. remarkably few human diseases have been attributed to genetic defects of the general importation machinery.31:91-123. Unless most disorders caused by disruption of the general importation machinery are incompatible with life. usually GTPases. Most. or leader peptide) is cleaved to release the mature protein. Of the four. chaperones needed for the unfolding and refolding of mitochondrially targeted proteins as they transit through the import receptors and are directed to the appropriate compartment. only Fis1p is an integral part of mitochondria. where mitochondria must travel a huge distance from the cell soma to the neuromuscular junction. Among the components of the import machinery. an MIA pathway protein located in the IMS (Roesch et al. For ﬁssion to occur. 2002). are members of the heat shock protein (HSP) family. Mdv1p (mitochondrial division protein). The import machinery consists of polymeric translocases in the outer membrane (TOM) or the inner membrane (TIM). we can expect more such disorders to be identiﬁed in the near future. Fis1p (ﬁssion-related protein). Fis1p recruits Dnm1p to the organelle via the bridge proteins.HSP: hereditary spastic paraplegia SPG: spastic paraplegia by the IMM). Mitochondria travel on microtubular rails. 104 DiMauro · Schon . Annu. 2002). usually located at the N-terminus of the protein. 1990) and PDHC deﬁciency (Takakubo et al.org by Columbia University on 01/19/12. 1995). TOM and TIM sort out incoming polypeptides to the proper compartments (Chacinska & Rehling 2004). called kinesins (when mitochondria travel downstream) or dyneins (when they travel upstream). 2003). Dnm1p then forms an evertightening spiral collar around the organelle.annualreviews. fuse. composed of nearly 60 polypeptides. and a mitochondrial import and assembly (MIA) pathway speciﬁc for a subset of IMS proteins (Gabriel et al. Downloaded from www. DISEASES CAUSED BY ABERRANT MITOCHONDRIAL DYNAMICS This relatively new area of interest for clinical neuroscientists has already yielded instructive results and is sure to provide many more in the coming years. at least four proteins are required for mitochondrial ﬁssion: Dnm1p (dynaminrelated protein). mitochondria move. located in the outer membrane. propelled by motor proteins. In collaboration with a sorting and assembly machinery (SAM). mitochondrial proteins (especially those destined for the IMM and the matrix) have well-deﬁned targeting signals. which severs the mitochondrion by strangulation (Chan 2006). as suggested by Fenton (1995). but not all. and divide within cells. two proteins are required in yeast: Fzo1p (the yeast homolog of the Drosophila fuzzy onion protein) and Ugo1p (ugo is Japanese for fusion). Neurosci. For personal use only. The ﬁrst mitochondrial motility defect was identiﬁed in a family with autosomal dominant hereditary spastic paraplegia type 10 (SPG10) and mutations in a gene encoding one of the kinesins (KIF5A): The mutation affects a region of the protein involved in microtubule binding (Fichera et al. the OMM and IMM must establish contact sites. Rev. For the opposite process of mitochondrial fusion.
(2006a) found mutations in MFN2 in affected members of six unrelated families with CMT6. beyond its role in fusion. 2004). 2006). MFN2. Downloaded from www.org by Columbia University on 01/19/12. is also required for remodeling the cristae (Cipolat et al. OPA1. 2000). even though most patients with CMT: Charcot-Marie Tooth www. which is located in the OMM and which regulates the mitochondrial network (Niemann et al. For personal use only. an IMM protein. A remarkable example of the underlying connections between mitochondrial movement and ostensibly disparate diseases is CharcotMarie-Tooth disease type 6 (CMT6). mutations in GDAP1. Genes boxed in yellow have been associated with neurodegenerative or psychiatric diseases (disease abbreviations in red ). However. severe.annualreviews. of LHON and are characterized by maldistribution of mitochondria in affected cells (Alexander et al. 2008.31:91-123. 2000. Rev. one of them had a missense mutation (R94W) identical to that in some patients with CMT2A. A recent review of 62 unrelated axonal CMT families revealed MFN2 mutations in 26 patients from 15 families. Moreover. Neurosci. 2005. cause CMT type 4A. which is characterized by the coexistence of peripheral neuropathy and optic atrophy. An underlying problem in mitochondrial movement presumably causes both peripheral and optic neuropathy. 2005). 2006) together with PARL (presenilin-associated rhomboid like). Black dots denote reported interactions between proteins. Zuchner et al. as it were. an IMS-localized protein (Pellegrini & Scorrano 2007). earlyonset form of either demyelinating or axonal neuropathy (Pedrola et al. Notably. which suggests that this is a major cause of axonal CMT2A (Chung et al. Mutations in the second mitofusin gene. the Mendelian counterpart. Mutations in OPA1 cause autosomal dominant optic atrophy (DOA). cause an autosomal dominant axonal variant of Charcot-Marie-Tooth disease (CMT type 2A) (Lawson et al.annualreviews. Mitochondrially targeted gene products are in bold. 2005) (Figure 8). as sometimes seen in LHON patients. OPA1 interacts with mitofusin 1 (MFN1) to promote fusion (Cipolat et al. Delettre et al. In addition.org • Mitochondrial Disorders in the Nervous System 105 . optic atrophy onset is followed in many patients by slow vision recovery. the gene encoding ganglioside-induced differentiation protein 1. an autosomal recessive. Mutations in the human orthologs of Mgm1p (OPA1) and Fzo1p (MFN2 or mitofusin 2) have been associated with human diseases.Microtubule Dynein/ dynactin DISC1 SCZD DNCH1 NUDEL YWHAE MDS YWHAZ LRRK2 FPD PINK1 FPD PARKIN FPD GDAP1 CMT4A Synuclein FPD Kinesins KIF5A SPG10 Spastin SPG4 Atlastin SPG3A Spastin SPG4 Cytosol HTT HD DYNCL1LI2 HAP1 Milton Miro MFN1 MFN2 CMT6 CMT2A Annu. OMM DJ-1 FPD HTRA2 FPD IMS OPA1 (large) DOA PARL OPA1 (small) DOA IMM HSPD1 SPG13 AFG3L1 AFG3L2 Matrix Paraplegin SPG7 Figure 8 Selected genes associated with mitochondrial dynamics. 2004). Suchner et al.
and distribution in ﬁbroblasts from an infant with a syndrome of encephalopathy.3. For personal use only. Rev. in fact. Two neuronal migration disorders. 1996)] generate excessive reactive oxygen species (ROS). the late Anita Harding posited the role of mitochondria in normal aging with her usual wit: “Growing Old: The Most Common Mitochondrial Disease of All?” (Harding 1992). shape. are associated with deletions on chromosome 17p13. 2006). The main objection to this hypothesis came from clinical experience because the mutation loads recorded in most postmitotic tissues during normal aging are at least one order of magnitude lower than those found · Schon . encoding the 14-3-3 protein ε isoform (YWHAE). which postulates a vicious cycle whereby somatic mtDNA mutations [predominantly deletions (Pallotti et al. and DISC1 (deleted in schizophrenia 1) (Millar et al. 2007).MFN2 mutations do not have optic atrophy. 2005). In yeast. long-range PCR).org by Columbia University on 01/19/12. putamen. A mitochondrial import defect may be related to impaired neuronal migration (Figure 8). YWHAZ is. Downloaded from www. the homolog of human YWHAE (Bmh1p. These ﬁndings are consistent with the almost 40-year-old “mitochondrial theory of aging” (Harman 1972). which is why it is also called the mitochondrial import stimulating factor subunit L (MSFL) (Alam et al. 1992). it is not too surprising that mutations in genes controlling mitochondrial motility may also affect other organelles. Last year. 1994). Millar et al. Her comments concerned an article documenting the age-related accumulation of the “common” 4977-bp mtDNA deletion (Schon et al. AGING AND LATE-ONSET NEURODEGENERATIVE DISORDERS In the title of a 1992 News & Views article for Nature Genetics. 2006. Because mitochondria are not the only cargoes to be moved around the cell. 2005. 14-3-3εαβγ) interacts with 106 DiMauro Annu. or ﬁssion (Table 4). gene DNM1L) (Waterham et al. is invariably deleted in patients with MDS lissencephaly (Toyo-oka et al. in turn. fusion. YWHAE is a cytoplasmic chaperone that targets precursor proteins to the mitochondria. Both mitochondria and peroxisomes had abnormal size. 2005). isolated lissencephaly sequence (ILS) and the Miller-Dieker syndrome (MDS). using more sophisticated techniques (laser microdissection. Ikuta et al. but especially in the caudate. whereas a second gene at this locus. Neurosci. Taylor et al. 2008. These diseases are only the proverbial tip of what will be found to be an iceberg of human neurodegenerative disorders directly or indirectly linked to abnormal mitochondrial motility. present in mitochondria (Schindler et al. Mutations in LIS1 (gene PAFAH1B1) cause ILS. whereas altered expression of both FEZ1 and DISC1 caused mitochondrial morphology and mobility defects (Ikuta et al. Kraytsberg et al. 2003). two groups conﬁrmed the age-related accumulation of somatic and clonal mtDNA deletions in substantia nigra and showed that neurons with high mutation loads were COX-negative (Bender et al. lactic acidosis. 14-3-3ζ) (Chaudhri et al. and most patients with OPA1 mutations do not have CMT. 2007. and these. the homolog of human YWHAZ (Bmh2p. 1989) in human brain. NUDEL targets dynein to microtubule ends through LIS1 (Li et al. loss of YWHAE may well affect neuronal migration either by disrupting the trafﬁcking of these latter proteins to mitochondria or by interdicting the binding of mitochondria to dynein.annualreviews. Thus. FEZ1 (fasciculation and elongation protein zeta-1) (Ikuta et al. 2003).31:91-123. optic atrophy. YWHAE interacts with three other proteins that not only are required for neuronal migration but also are known to associate with mitochondria: NUDEL (nuclear distribution protein nudE-like 1) (Brandon et al. The patient’s nuclear background may inﬂuence the penetrance of the mitochondrial trafﬁcking defect. single-molecule PCR. and a heterozygous dominant mutation in the human ortholog of yeast Dnm1p called dynamin-like or dynamin-related protein 1 (DLP1/DRP1. 2006. 2007). 2005). 2007). 2003). and substantia nigra (Soong et al. further damage mtDNA.
and amyotrophic lateral sclerosis. Overall...g. although neurons from patients with Parkinson disease do not contain signiﬁcantly more -mtDNAs than did age-matched controls (Bender et al. In fact. lationship of mitochondrial biology to neurodegeneration and then the speciﬁc diseases attributed to mutations in nuclear-encoded proteins.annualreviews. 2004). as a general rule.annualreviews. www. strokes) or subacute (e. seizures.org by Columbia University on 01/19/12. ataxia. in fact precipitous. Parkinson disease. and programmed cell death—cause chronic clinical problems of much later onset. Alzheimer disease. in children or in young adults. 2006). neuropathy) clinical problems that manifest early in life. However. aging of transgenic mice that express a proofreading-deﬁcient POLG (Khrapko et al.org • Mitochondrial Disorders in the Nervous System 107 . in patients with primary pathogenic mtDNA deletions (e.Table 4 Disease Diseases associated with defects in mitochondrial dynamicsa Gene OPA1 MFN2 GDAP1 MFN2 SPG3A SPAST SPG7 KIF5A SPG20 REEP1 DNM1L HD YWHAE Mitofusin 2 Ganglioside-induced differentiation protein 1 Mitofusin 2 Atlastin (associated with spastin) Spastin (microtubule severing protein) Paraplegin (AAA protease) Kinesin heavy chain Spartin (microtubule-interacting protein?) Receptor expression-enhancing protein Dynamin-related protein DLP1 Huntingtin (binds HAP1) 14-3-3ε protein Protein Dynamin-related GTPase Dominant optic atrophy (DOA) CMT type 2A CMT type 4A CMT type 6 AD-HDP type 3A Annu. most of them targeted to the mitochondria (Tieu & Przedborski 2006). 2006). Downloaded from www. 2008.31:91-123. Kujoth et al. The observation that many of these neurons are functionally impaired (COX-negative) makes conceivable the second step in the vicious cycle: excessive ROS generation. these disorders cause acute (e.g. Table 2). Although the mitochondrial theory of aging in and by itself does not explain either natural aging or late-onset neurodegenerative diseases. organellar dynamics. the proportion of -mtDNA measured in single neurons of the substantia nigra from aged normal individuals approaches or surpasses the estimated pathogenic threshold (Bender et al. AD-HSP type 4 AR-HSP type 7 AD-HSP type 10 AR-HSP type 20 AD-HSP type 31 Infantile microcephaly Huntington disease Lissencephaly (Miller-Dieker) a Genes encoding mitochondrially targeted proteins are in bold.. However. 2005. A dramatic example of the importance (but not necessarily the functional signiﬁcance) of nuclear factors is the precocious. Rev. KSS. genetic defects in mitochondrial functions that do not directly impact the respiratory chain—such as protein import. it is no stretch of the imagination to envision the same kinds of mitochondrial involvement even in the far-more-common sporadic presentations of these devastating disorders. Neurosci.g. together with nuclear genetic factors. 2006. Trifunovic et al. 2006. Kraytsberg et al. now that we have begun to appreciate that the familial forms of the Big Three involve mitochondrial function in the guise of altered organellar dynamics. it almost certainly plays a role in both conditions. highly reminiscent of the three more common age-related and apparently sporadic neurodegenerative disorders. The role of nuclear-encoded mitochondrial factors in neurodegenerative disorders can be approached by considering ﬁrst the general re- YOU CAN PAY ME NOW OR YOU CAN PAY ME LATER The classic mitochondrial diseases known as the mitochondrial encephalomyopathies are caused by mutations in the mitochondrial or nuclear genome that affect the respiratory chain directly. For personal use only.
and the mitochondrial permeability transition. Excessive ROS production (oxidative stress) is considered a central feature in the pathogenesis of all neurodegenerative disorders (Beal 2005). and maximum lifespan potentials in ﬁve different mammalian species (Wright et al. through the adaptor molecule Apaf-1.Mitochondria and Neurodegeneration FRDA: Friedreich ataxia Cell death in neurodegenerative diseases usually occurs by apoptosis. peripheral neuropathy with areﬂexia. it may be present in the OMM at sites of contact with the IMM. The observation that during apoptosis the normally tubular mitochondrial network becomes fragmented. (RONS). suggests a regulatory role for mitochondrial ﬁssion and fusion. and that the proapoptotic molecule Bax colocalizes with the fusionrelated proteins DRP1 and MFN2 (Newmeyer & Ferguson-Miller 2003). A pathogenic role for ROS in age-related neurodegeneration is also suggested by the correlation between rates of formation of mitochondrial reactive oxygen and nitrogen species Annu. which block IAP (inhibitor of apoptosis) proteins to activate cell death caspases. their life-supporting functions are clearly linked to their death-promoting activity. 2008. more commonly by the intrinsic mitochondrial pathway than by the extrinsic cell-signaling pathway. where Bid and Bcl-2 also cluster (Newmeyer & Ferguson-Miller 2003). Downloaded from www. mitochondria are not merely passive containers capable of leaking cytochrome c: Rather. The permeability transition (PT) refers to a still largely hypothetical pore composed of cyclophilin D and the ANT1 protein in the IMM and of the voltage-dependent anion channel (VDAC) and the peripheral benzodiazepine receptor in the OMM. with the unavoidably associated generation of ROS. progressive limb and gait ataxia. Sustained opening of the PT pore is considered an obligatory step in apoptosis. Also. mitochondrial fusion and ﬁssion. For personal use only. Neurosci. which explains the popularity of ROSscavenging compounds. cardiolipin has many functions beyond being a scaffold for the respiratory chain: One such function may be to favor apoptosis through Bax-mediated permeabilization of the OMM. 2006c. and most patients are homozygous for a GAA trinucleotide repeat expansion in the ﬁrst intron of FXN. not just an executioner in apoptosis. is encoded by a gene (FXN) on chromosome 9q13. frataxin. As mentioned above. These modulating factors include the respiratory chain activity. As an obvious example of the respiratory chain inﬂuence. calcium homeostasis. rates of neurodegeneration in brain and retina. The mutated mitochondrial protein. pyramidal signs. and residual 108 DiMauro · Schon . and also stress and survival signals. Rev. regulate the release of cytochrome c from the ISS into the cytoplasm. These are loss-of-function mutations. The hallmark neuropathology of FRDA is degeneration of the spinocerebellar tracts and large sensory neurons. cytochrome c is a vital watersoluble electron carrier. such as CoQ10 or analogous molecules. Although cardiolipin is predominantly a component of the IMM.annualreviews. such as manganese superoxide dismutase (SOD2) and glutathione peroxidase. in therapeutic trials (DiMauro et al. hypertrophic cardiomyopathy. However.org by Columbia University on 01/19/12. in the intrinsic pathway of apoptosis. and increased incidence of diabetes. by regulating the release of cytochrome c from the IMS to the cytosol. Proapoptotic signals can also release proteins such as Smac/DIABLO and Omi/HTRA2. ROS are normal byproducts of the respiratory chain activity.31:91-123. Proapoptotic and antiapoptotic members of the Bcl-2 family. Neurodegenerative Diseases Caused by Mutations in Nuclear-Encoded Proteins Targeted to Mitochondria Friedreich ataxia (FRDA) is an autosomal recessive disorder characterized clinically by early onset (before 25 years of age). 2004). The intrinsic pathway controls activation of caspase 9. the lipid composition of the mitochondrial membranes. Shults & Schapira 2001). and their concentration is controlled by mitochondrial antioxidant enzymes.
and indeed. We have already discussed two different mitochondrial causes of autosomal dominant HSP: one a defect in mitochondrial protein importation caused by mutations in SPG13. as discussed above. antioxidant defenses are decreased in cultured cells from FRDA patients (Chantrel-Groussard et al. again implicating cargo trafﬁc on microtubules (and almost certainly mitochondria) in the pathogenesis of the disorder. To worsen the situation. Spartin has a microtubule interacting and trafﬁcking (MIT) domain at its N-terminus (interestingly. Autosomal dominant HSP type 4 (SPG4) is caused by mutations in spastin (gene SPAST). 2006). and the mitochondrial theory of aging. implying yet again the role of mitochondrial trafﬁcking in the pathogenesis of this syndromic group (Lu et al.org by Columbia University on 01/19/12. the respiratory chain (Claypool et al. Parkinson disease (PD) is a predominantly sporadic late-onset disorder. www. 2006). Because AAA proteases have a quality control function ensuring that unassembled respiratory chain subunits are degraded. ultimately. causing oxidative damage and further mitochondrial enzyme inactivation. and mutations in the gene encoding this protein (SPG3A) also cause HSP (autosomal dominant HSP type 3A). Spastin’s binding partner is known as atlastin (Sanderson et al. autosomal dominant HSP type 31 (SPG31) is caused by mutations in receptor expression-enhancing protein 1 (REEP1). Iron accumulation increases ROS generation by the Fenton reaction. 2008. 2006b). encoding the chaperonin HSP60 (HSP here stands for heat shock protein). and the detoxiﬁcation of iron. More controversial is the pathogenesis of an autosomal recessive form of HSP caused by mutations in a gene (SPG7) encoding paraplegin. Nolden et al. For personal use only. paradoxically. Thus.org • Mitochondrial Disorders in the Nervous System 109 . age-related accumulation of somatic mtDNA deletions in the substantia nigra (coupled with biochemical evidence of complex I deﬁciency). including aconitase and complexes I. a conditional neuronal frataxin knockout mouse showed neither evidence of oxidative stress nor improvement with antioxidants (Seznec et al. with its nonfamilial. 2005). 2006). II. 2006).annualreviews. Finally.31:91-123. 2006. a component of the large ribosomal subunit tightly bound to the IMM (Claypool et al. a protein highly homologous to the AAA family of mitochondrial proteases (Casari et al. provided an attractive pathogenic explanation. and the other a defect of mitochondrial behavior caused by mutations in the kinesin KIF5A. presumably a consequence of an inability of mutated spastin to sever microtubules (McDermott et al. a microtubule-severing protein located in the cytoplasm. at least on the cardiopathy (Schulz et al. Loss of frataxin causes impaired mitochondrial iron storage and metabolism and defects in mitochondrial enzymes containing ISCs. this mechanism PD: Parkinson disease Annu. an OMM protein (Lu et al. Because mitochondria must be attached to microtubules for them to travel down axons. 1998). FRDA pathogenesis is controversial because frataxin is involved in the formation of nonheme iron-sulfur clusters (ISCs). a mutated paraplegin may impair mtDNA translation. Rev. its mitochondrial targeting signal is located at the C-terminus). and III. disruption of this connection should affect mitochondrial mobility. Downloaded from www. Autosomal recessive HSP type 20 (also called Troyer syndrome) is due to mutations in spartin (gene SPG20). cells of SPG4 patients showed an abnormal perinuclear clustering of mitochondria. another function of paraplegin seems to involve process- ing MRPL32. heme biosynthesis. Hereditary spastic paraplegia (HSP) is the term for a group of clinically similar disorders rather than a speciﬁc clinical entity. in which case this form of HSP would belong with the subgroup of intergenomic communication disorders discussed above. 2001). 2000).annualreviews.frataxin expression level correlates with the severity of the clinical phenotype. Although. Although the pathogenic role of oxidative stress in FRDA seemed bolstered by the beneﬁcial effects of the antioxidant idebenone. 2003). a mitochondrial protein of unknown function (Zuchner et al. Neurosci. 2005). However. a mutated paraplegin may result in an accumulation of defective subunits “choking” the importation machinery (similar to mutations in HSP60) and.
mutations in the SNCA gene cause autosomal dominant PD (Polymeropoulos et al.31:91-123. and a polymorphism in the same gene seems to predispose to PD development. 2006). Huntington disease (HD). 2005) whose precise function is unknown. To date. 2005). four pathogenic scenarios all involve mitochondrial dysfunction. and (d ) transgenic mice expressing mutant αsynuclein show neuronal degeneration. All these proteins interact directly or indirectly with mitochondria and seem to affect apoptosis. accumulation of intraneural inclusions. 2004). 2006). The third pathogenic mechanism in a sense includes the previous two and suggests that mutant HTT impairs mitochondrial function in Annu. an autosomal dominant disorder. The second scenario is based on evidence that polyglutamine accumulation impairs calcium handling. PARK7 (locus PARK7). patients with PD and parkin mutations have decreased complex I in leukocytes (Muftuoglu et al. and it can be seen even in young patients without PEO (Davidzon et al. Rev. PINK1 (locus PARK6). 2008. which encodes a protein called huntingtin (HTT). Although HTT is not a mitochondrial protein. where they likely have an antiapoptotic function. good evidence demonstrates that both wild-type and mutant DJ-1 proteins are present in mitochondria (matrix and IMS) (Zhang et al. Both direct and indirect biochemical evidence also show impaired energy production because the activities of respiratory chain complexes II and III were decreased in postmortem HD brains. Although mutations in DJ-1 were thought to abolish the oxidation-induced localization of the protein to mitochondria (Canet-Aviles et al. Selective degeneration of striatal neurons and marked atrophy of caudate and putamen occur. HD is caused by abnormal expansion of a CAG repeat in the HD gene on chromosome 4. when overexpressed. but which. encoding PTEN-induced putative kinase 1.org by Columbia University on 01/19/12. if the diagnostic criteria of the London Brain Bank are applied strictly) is familial more often than thought until ﬁve years ago (Hardy et al. SNCA (locus PARK1/4). 2005a). In humans. six nuclear genes have been implicated: PARK2 (disease locus PARK2). and HTRA2 (locus PARK13) encoding Omi/HTRA2. For personal use only. when mutated. Downloaded from www. where it has a protective role against mitochondrial swelling caused by ceramide-induced apoptosis (Darios et al. or PINK1. LRRK2 (locus PARK8). PD (or parkinsonism. (b) transgenic mice overexpressing α-synuclein in neurons are overly sensitive to MPTP. (2005) found a mutation in HTRA2 in four sporadic patients with PD. · Schon . protects against neuronal apoptosis (Petit et al. encoding α-synuclein. emotional problems. α-synuclein is a cytosolic protein. (c) α-synuclein-deﬁcient mice are more resistant to respiratory chain inhibitors. encoding dardarin. 2004). and complex IV deﬁciency in the spinal cord. The ﬁrst scenario postulates an energy metabolism defect and is based on magnetic resonance spectroscopy (MRS) of the brain (showing lactate peaks in the occipital cortex and basal ganglia) and of muscle (showing decreased PCr/Pi ratios). 2003). 1997). encoding parkin. Neurosci. causing calcium-induced permeability transition and cytochrome c release (Choo et al.annualreviews. Parkin is a ubiquitin E3 ligase associated with the OMM. penetrates fully by mid-adult life and is characterized by choreoathetotic movements. and dementia. Mutations in PARK2 have been associated with autosomal recessive PD. Autosomal recessive parkinsonism is not uncommon in patients with PEO and mutations in POLG. Omi/HTRA2 is a serine protease localized to the mitochondrial IMS and released into the cytosol upon apoptosis induction. As further evidence of a mitochondrial role for parkin. encoding DJ-1 (Hardy et al. Strauss et al. 2006). but its functional relationship with mitochondria is revealed by several observations: (a) Overexpression of mutant α-synuclein in cell cultures im110 DiMauro pairs the respiratory chain and induces oxidative damage. and inhibition of complex II by malonate in experimental animals caused pathological lesions resembling those of human HD. PINK1 is a mitochondrial kinase (Silvestri et al.HD: Huntington disease per se is not sufﬁcient to explain sporadic PD. causes early-onset recessive PD and. 2003).
Conversely. 1992). 1999. and respiratory chain deﬁciency (Bonilla et al. HAP1 was localized to small puncta in both the nucleus and the mitochondria (Gutekunst et al. HAP1 is a cytosolic protein that associates with microtubules and other membranous compartments of the cell. and investigators assume that they cause a toxic gain of function. HAP1. Neurosci. In addition. SOD1 is present in both the cytosol and in the IMS (Sturtz et al. Most pathogenic mutations do not impair SOD1 activity. sporadic disorder typically affecting both lower (anterior horn cells of the spinal cord) and upper (cortical) motor neurons.and extracellular fragments of uncertain function.org • Mitochondrial Disorders in the Nervous System 111 . 1985). albeit early-onset. The current view is that APP is located predominantly in the plasma membrane. 1993. and ∼20% of these harbor mutations in the Cu.g. presenilin 1 (PS1. gene PSEN1). Kish et al.org by Columbia University on 01/19/12. and by the impaired mitochondrial functions (respiratory chain and calcium homeostasis) seen in transgenic mice. etc. consisting mainly of hyperphosphorylated forms of the microtubuleassociated protein tau (Goedert & Spillantini 2006. one patient with primary mitochondrial disease (a microdeletion in the COX I gene of mtDNA) had a typical. and of neuroﬁbrillary tangles. 2004). 2007). Variants in two genes predispose people to SAD: apolipoprotein E isoform 4 (APOE4) (Corder et al. 1998). 2004). and perhaps most provocative. Mitochondrial involvement in FALS is suggested by the early mitochondrial degeneration observed in motor neurons from patients and transgenic animals.annualreviews. PGC-1α (peroxisome proliferators-activated receptor-γ coactivator 1α) is a master transcriptional coactivator that controls mitochondrial biogenesis and oxidative phosphorylation (Greenamyre 2007). 1993).Zn-superoxide dismutase 1 (SOD1) gene. 2007). About 5%–10% of patients have a familial form of ALS (FALS). with a relatively long course (Mattson 2004). Most AD cases are sporadic.annualreviews. ALS phenotype (Comi et al. Avadhani’s group showed by genetic dissection and expression of APP ALS: amyotrophic lateral sclerosis FALS: Familial ALS AD: Alzheimer disease FAD: familial AD Annu. β-. Rev.31:91-123. especially in the cortex and the hippocampus. hinging mainly on ﬁndings related to both APP and PS1. Roberson et al. However.. Abundant evidence indicates that mitochondria are affected in AD. 1999. and presenilin 2 (PS2. www. where it is cleaved in a series of proteolytic events (e. 1998). Transgenic mouse models overexpressing mutant SOD1 also develop motor neuron degeneration. Amyotrophic lateral sclerosis (ALS) is a late-onset. consisting mainly of β-amyloid (Aβ). causing widespread paralysis and premature death. a neuronal sorting receptor (Rogaeva et al. but three genes have been identiﬁed in the familial form (FAD): amyloid precursor protein (APP).a more general way. using immuno-electron microscopy. including mitochondria (Gutekunst et al. Downloaded from www. and γ-secretases) to release intra. The two main histopathological hallmarks of AD are the accumulation of extracellular neuritic plaques. 1998). Li et al. mitochondrial metabolic enzyme deﬁciency (Mastrogiacomo et al. Studies also report respiratory chain abnormalities in spinal cord of sporadic ALS patients (Borthwick et al. by the presence of mutant SOD1 and of aggregates containing mutant SOD1 in the mitochondrial matrix and IMS (Liu et al. 1993) and SORL1. by α-. 2001). Wiedemann et al. including reduction in brain energy metabolism shown by positron emission tomography (Azari et al. a direct role for mitochondria in AD pathogenesis has been controversial. HTT binds to huntingtininteracting protein 1 (HAP1). 2002). 1998). However. The relationship between HTT. 2008. gene PSEN2). a physical interaction that impacts organellar mobility in this disease may exist between HTT and mitochondria. Alzheimer disease (AD) is a neurodegenerative dementing disorder of late onset. Sheu et al. 1997. However. 2003) and that mutant HTT impairs axonal trafﬁcking in mammalian neurons (Trushina et al. Fourth. HAP1 interacts with the p150Glued subunit of dynactin (DYNC1LI2) (Engelender et al. by repressing PGC-1αregulated gene transcription of many nucleusencoded mitochondrial genes. For personal use only. Studies show progressive neuronal loss. and dynactin may explain the observation that microtubules are destabilized in HD (Trushina et al.
2004). First. to localize PS1 to the rat mitochondrial inner membrane (Ankarcrona & Hultenby 2002. all three proteins have been localized to rat 112 DiMauro Annu. For the sake of order.constructs in vitro that the APP protein contains a possible mitochondrial targeting signal at its N-terminus (Anandatheerthavarada et al.org by Columbia University on 01/19/12. 2003). Vetrivel et al. let us consider separately the psychiatric manifestations of primary mitochondrial diseases and the evidence of mitochondrial dysfunction in patients with isolated primary psychiatric illnesses. endosomes/lysosomes (Runz et al. where they are especially enriched at intercellular contacts known as adherens junctions (Marambaud et al. α. to mitochondria has not been conﬁrmed or demonstrated by other. Hansson et al. Researchers disagree with regard to PS1. 1999. This possibility is supported by two observations. 2004). This result was consistent with (a) the identiﬁcation of Aβ42 in mitochondria (Lustbader et al. including PS1. a PS1 mutation (M146V) in a mouse PS1 knock-in model impairs axonal transport and also increases tau phosphorylation (Pigino et al. 2000). Using immunoelectron microscopy and Western blotting. Besides PS1. 2008. They then showed that nonglycosylated full-length and C-terminal truncated APP accumulates exclusively in the mitochondrial protein import channels in AD brains but not in age-matched controls (Devi et al. Given that mitochondria play a role in the pathogenesis of several neurodegenerative diseases (Figure 8). 2003). PEN2. We have reported preliminary data on a large group of MELAS and MERRF families (102 persons from 30 kindreds). have been found in both sporadic AD patients and in transgenic mouse models of FAD (Stokin et al. 2002). more deﬁnitive. 2005). and vesicles. Rev. However. Downloaded from www. localization of γ-secretase subunits. mostly severe depression. except by one group that used Western blotting and immunoelectron microscopy. Siman & Velji 2003). it would not be unreasonable to invoke similar mechanisms for AD. including not only patients but also their · Schon . 1996). 2004.annualreviews. Although the literature is replete with anecdotal reports of psychiatric problems. Second. mitochondria (Hansson et al. and especially a mechanism involving mitochondrial movement and localization (Kins et al. 2006). but at present there is no coherent explanation as to how this might be accomplished.. it is unclear how Aβ could be derived from its precursor APP within mitochondria. the γ-secretase complex contains at least three other proteins: APH1. axonal defects. and (c) the ﬁnding that β-amyloid inhibits respiratory chain function in isolated rat brain mitochondria (Casley et al. there have been few systematic neuropsychiatric studies of large cohorts of patients with known mitochondrial diseases.and β-secretases) have not been found in mitochondria. organelles. 2002). methods. 2006).31:91-123. Using immunohistochemical techniques. 2004). These include the endoplasmic reticulum (ER) (Walter et al. Manczak et al. Neurosci. not immunohistochemistry. consisting of swellings that accumulate abnormal amounts of microtubule-associated and molecular motor proteins. it is hardly surprising that primary mitochondrial disorders often cause cognitive deﬁcits: dementia in adults and mental retardation or neuropsychological regression in children. and nicastrin (De Strooper 2003). Aβ could be imported into mitochondria. given that the putative requisite initial processing proteases (e.g. the Golgi apparatus (Annaert et al. and the plasma membrane (Schwarzman et al. 2006b). PS1 has not been found in mitochondria. 2006). the nuclear envelope (Honda et al. PS1 has been localized to numerous membranous compartments in cells. Researchers have paid comparatively less attention to the relationship between psychiatric diseases and mitochondrial dysfunction. 2002. For personal use only. in patients with mtDNArelated diseases (DiMauro et al. MITOCHONDRIAL PSYCHIATRY Given the brain’s high dependence on oxidative metabolism. 1999). However. a mitochondrial matrix protein involved in fatty acid metabolism (Lustbader et al. type 10 (HADH2). 2004). (b) the observation that Aβ binds to 17-β-hydroxysteroid dehydrogenase.
and multiple mtDNA deletions. mitochondria perform varied functions that are important for cell life and death. However. and POLG (DiMauro et al. suggesting a role of this protein in controlling mitochondrial dynamics (Millar et al. Among the Mendelian mitochondrial diseases. and impaired mtDNA replication (Kakiuchi et al. are similar to those proposed for neurodegenerative diseases. many of which. thalamus) and its involvement with neuronal migration. PEO. The ﬁnding that even asymptomatic carriers of the MELAS mutation were prone to depression suggested that psychiatric problems might be an early clinical expression of the mutation. A second. a pivotal gene in the endoplasmic reticulum stress response (Kakiuchi et al. 1990). and Taiwanese populations (Roberts 2007) and extended to bipolar disorder (Maeda et al. Although maternal inheritance of bipolar disorder had been suggested by a higher-thanexpected frequency of affected mothers and increased risk of illness in maternal relatives. Psychiatric problems are especially common in patients harboring mutations in ANT1. and NUDEL. and synaptic plasticity support the pathogenic role of genetic variants in psychiatric disorders. These include alterations of calcium homeostasis (Kato et al. showing cerebral lactic acidosis in asymptomatic MELAS relatives and a correlation between neuropsychological scores and ventricular lactate levels (Kaufmann et al. In MERRF families with the A8344G mutation. LIS1. but 22% of asymptomatic and 29% of oligosymptomatic carriers also had depressive traits. 2004). hippocampus. 2002). so called because a disruption of this gene by the chromosome 1 breakpoint of a balanced t(1.org • Mitochondrial Disorders in the Nervous System . 2006). Annu. Overexpression of DISC1 in COS-7 cells disrupts mitochondrial organization and leads to the formation of ringlike structures. and none of the asymptomatic carriers reported depressive symptoms. mutations in mtDNA have been excluded as causes of the disease (Kirk et al. 80% of fully symptomatic patients. 2002). 2006b). Although its precise role remains unclear. in fact. American. Downloaded from www.org by Columbia University on 01/19/12. The distribution of DISC1 in the developing and adult brain (frontal cortex. a foreign guest that took up permanent residence in all our cells. 20% of oligosymptomatic carriers. and programmed cell death. and related. participates in such a wide array of neurological disorders. consideration is that there is much more to mitochondria than the standard textbook gloss that they are the powerhouses of the cell that only produce ATP. PEO1. at least indirectly. calcium homeostasis. Neurosci.annualreviews.11) translocation did. downregulation of genes controlling mitochondrial energy metabolism (Konradi et al. from LS in infancy to AD in old age. which is also supported by correlative neuropsychological and MRS studies. 2003). DISC1 bound predominantly to mitochondria (James et al. mitochondrial dysfunction may still be involved in bipolar disorder pathogenesis through several pathogenic mechanisms. in neurodegenerative diseases (Figure 8). including ROS generation. and the pathogenesis of any mitochondrial disease 113 www. Japanese. 42% of fully symptomatic carriers reported depressive symptoms.31:91-123. including FEZ1. Besides ATP production. depression is frequent in patients with defects of intergenomic communication. compared with only 7% of the control group (Kaufmann et al. 2004). For personal use only. 2008.oligosymptomatic or asymptomatic maternal relatives. 2004) and interacted with several proteins. The ﬁrst is a sense of amazement that this small organelle. 1999). 2005). Another gene that has been highlighted in the pathogenesis of both bipolar disorder and schizophrenia is Disrupted in schizophrenia 1 (DISC1). 2005). not surprisingly. The association of DISC1 and schizophrenia was conﬁrmed in Finnish. cosegregate with schizophrenia and related mood disorders in a large Scottish family (St Clair et al. neurite outgrowth. Rev. which are also involved. In MELAS families (harboring the A3243G mutation). all possibly related to a change (-116C > G) in the promoter region of XBP1.annualreviews. CONCLUSIONS Two main concepts emerge from this overview of mitochondrial disorders in the nervous system.
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Trapp and Klaus-Armin Nave p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 247 Multifunctional Pattern-Generating Circuits K. Sawtell p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 1 Spike Timing–Dependent Plasticity: A Hebbian Learning Rule Natalia Caporale and Yang Dan p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p25 Balancing Structure and Function at Hippocampal Dendritic Spines Jennifer N. and Nathaniel B. Cullen p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 125 Role of Axonal Transport in Neurodegenerative Diseases Kurt J.org by Columbia University on 01/19/12. Petros. Miller p p p 151 Active and Passive Immunotherapy for Neurodegenerative Disorders David L. Moser. De Vos. Alexandra Rebsam. Rev. Neurosci. Mason p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 295 Volume 31.annualreviews. p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 271 Retinal Axon Growth at the Optic Chiasm: To Cross or Not to Cross Timothy J. and May-Britt Moser p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p69 Mitochondrial Disorders in the Nervous System Salvatore DiMauro and Eric A. Steven Ackerley. Angelaki and Kathleen E.31:91-123. Harris p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p47 Place Cells. Brody and David M.B. For personal use only. v . Kristan.J. Holtzman p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 175 Descending Pathways in Motor Control Roger N. and Christopher C.Annual Review of Neuroscience Contents Cerebellum-Like Structures and Their Implications for Cerebellar Function Curtis C. Bourne and Kristen M. and the Brain’s Spatial Representation System Edvard I. Lemon p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 195 Task Set and Prefrontal Cortex Katsuyuki Sakai p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 219 Multiple Sclerosis: An Immune or Neurodegenerative Disorder? Bruce D. 2008 Annu.L. and Carol A. Grierson. Briggman and W. Schon p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p91 Vestibular System: The Many Facets of a Multimodal Sense Dora E. Downloaded from www. 2008. Jr. Victor Han. Bell. Andrew J. Emilio Kropff. Grid Cells.
org/ vi Contents . Tsao and Margaret S. Neurosci. Volumes 22–31 p p p p p p p p p p p p p p p p p p p p p p p p p p p 591 Cumulative Index of Chapter Titles. Marla B. Graybiel p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 359 Mechanisms of Self-Motion Perception Kenneth H. Trapp p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 535 Signaling Mechanisms Linking Neuronal Activity to Gene Expression and Plasticity of the Nervous System Steven W. Volumes 22–31 p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 595 Errata An online log of corrections to Annual Review of Neuroscience articles may be found at http://neuro. Downloaded from www. Kuhl and Maritza Rivera-Gaxiola p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 511 Axon-Glial Signaling and the Glial Support of Axon Function Klaus-Armin Nave and Bruce D. Rev. Salinas and Yimin Zou p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 339 Habits.31:91-123. Livingstone p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 411 The Prion’s Elusive Reason for Being Adriano Aguzzi. Frank Baumann.Brain Circuits for the Internal Monitoring of Movements Marc A. Rituals.annualreviews. Huberman.annualreviews. and Juliane Bremer p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 439 Mechanisms Underlying Development of Visual Maps and Receptive Fields Andrew D. Wurtz p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 317 Wnt Signaling in Neural Circuit Assembly Patricia C.org by Columbia University on 01/19/12. Britten p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 389 Annu. 2008. and Barbara Chapman p p p p p p p p p p p p p p p p p p p p p p p p 479 Neural Substrates of Language Acquisition Patricia K. Greenberg p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 563 Indexes Cumulative Index of Contributing Authors. Flavell and Michael E. Feller. For personal use only. Sommer and Robert H. and the Evaluative Brain Ann M. Mechanisms of Face Perception Doris Y.
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