Molecular biology of amyotrophic lateral sclerosis: insights from genetics

Amyotrophic lateral sclerosis (ALS) is a paralytic disorder caused by motor neuron degeneration. Mutations in more than 50 human genes cause diverse types of motor neuron pathology. Moreover, defects in five Mendelian genes lead to motor neuron disease, with two mutations reproducing the ALS phenotype. Analyses of these genetic effects have generated new insights into the diverse molecular pathways involved in ALS pathogenesis. Here, we present an overview of the mechanisms for motor neuron death and of the role of non-neuronal cells in ALS.

[1]  Robert H. Brown,et al.  Caspase-3 Cleaves and Inactivates the Glutamate Transporter EAAT2* , 2006, Journal of Biological Chemistry.

[2]  Sergio Cocozza,et al.  Spastic Paraplegia and OXPHOS Impairment Caused by Mutations in Paraplegin, a Nuclear-Encoded Mitochondrial Metalloprotease , 1998, Cell.

[3]  S. Ennis,et al.  A novel candidate region for ALS on chromosome 14q11.2 , 2004, Neurology.

[4]  D. Figlewicz,et al.  Aggregation of Mutant Cu/Zn Superoxide Dismutase Proteins in a Culture Model of ALS , 1997, Journal of neuropathology and experimental neurology.

[5]  D. Macgowan,et al.  An ALS-like syndrome with new HIV infection and complete response to antiretroviral therapy , 2001, Neurology.

[6]  Robert H. Brown,et al.  An intersubunit disulfide bond prevents in vitro aggregation of a superoxide dismutase-1 mutant linked to familial amytrophic lateral sclerosis. , 2004, Biochemistry.

[7]  N. Bresolin,et al.  The first ALS2 missense mutation associated with JPLS reveals new aspects of alsin biological function. , 2006, Brain : a journal of neurology.

[8]  Zuoshang Xu,et al.  ALS-associated mutant SOD1G93A causes mitochondrial vacuolation by expansion of the intermembrane space and by involvement of SOD1 aggregation and peroxisomes , 2003, BMC Neuroscience.

[9]  E. Bigio,et al.  Conversion to the amyotrophic lateral sclerosis phenotype is associated with intermolecular linked insoluble aggregates of SOD1 in mitochondria. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[10]  J. Fink,et al.  NIPA1 gene mutations cause autosomal dominant hereditary spastic paraplegia (SPG6). , 2003, American journal of human genetics.

[11]  B. Rubin,et al.  Familial dysautonomia is caused by mutations of the IKAP gene. , 2001, American journal of human genetics.

[12]  Bertrand Fontaine,et al.  Spastin, a new AAA protein, is altered in the most frequent form of autosomal dominant spastic paraplegia , 1999, Nature Genetics.

[13]  T. Shows,et al.  Fine Assignment of 3-Hexosaminidase A ar-Subunit on 15823-q 24 by High Resolution In Situ Hybridization , 2006 .

[14]  J. Morrison,et al.  Transgenic mice expressing an altered murine superoxide dismutase gene provide an animal model of amyotrophic lateral sclerosis. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[15]  V. Meininger,et al.  Variants of the heavy neurofilament subunit are associated with the development of amyotrophic lateral sclerosis. , 1994, Human molecular genetics.

[16]  A. Munnich,et al.  Neurological phenotype in Waardenburg syndrome type 4 correlates with novel SOX10 truncating mutations and expression in developing brain. , 2000, American journal of human genetics.

[17]  D. Huylebroeck,et al.  Slowed conduction and thin myelination of peripheral nerves associated with mutant rho Guanine-nucleotide exchange factor 10. , 2003, American journal of human genetics.

[18]  M. Pericak-Vance,et al.  The gene encoding alsin, a protein with three guanine-nucleotide exchange factor domains, is mutated in a form of recessive amyotrophic lateral sclerosis , 2001, Nature Genetics.

[19]  Ahmet Hoke,et al.  Loss of ALS2 Function Is Insufficient to Trigger Motor Neuron Degeneration in Knock-Out Mice But Predisposes Neurons to Oxidative Stress , 2005, The Journal of Neuroscience.

[20]  Hiroshi Nishimune,et al.  Motoneuron Death Triggered by a Specific Pathway Downstream of Fas Potentiation by ALS-Linked SOD1 Mutations , 2002, Neuron.

[21]  J. Lupski,et al.  Mutations in the early growth response 2 (EGR2) gene are associated with hereditary myelinopathies , 1998, Nature Genetics.

[22]  D. Turnbull,et al.  Motor neuron disease in a patient with a mitochondrial tRNAIle mutation , 2006, Annals of neurology.

[23]  A Al-Chalabi,et al.  Deletions of the heavy neurofilament subunit tail in amyotrophic lateral sclerosis. , 1999, Human molecular genetics.

[24]  Robert H. Brown,et al.  SPTLC1 is mutated in hereditary sensory neuropathy, type 1 , 2001, Nature Genetics.

[25]  J. Powell,et al.  Copper and zinc levels in familial amyotrophic lateral sclerosis patients with cuznsod gene mutations , 1997, Annals of neurology.

[26]  金蔵 孝介.  Alsin, the product of ALS2 gene, suppresses SOD1 mutant neurotoxicity through RhoGEF domain by interacting with SOD1 mutants , 2005 .

[27]  M. Brodsky,et al.  Heterozygous mutations of the kinesin KIF21A in congenital fibrosis of the extraocular muscles type 1 (CFEOM1) , 2003, Nature Genetics.

[28]  J. Lupski,et al.  Charcot-Marie-Tooth disease type 1A: molecular mechanisms of gene dosage and point mutation underlying a common inherited peripheral neuropathy. , 1991, International journal of neurology.

[29]  P K Thomas,et al.  N-myc downstream-regulated gene 1 is mutated in hereditary motor and sensory neuropathy-Lom. , 2000, American journal of human genetics.

[30]  P. Andersen,et al.  Phenotypic heterogeneity in motor neuron disease patients with CuZn-superoxide dismutase mutations in Scandinavia. , 1997, Brain : a journal of neurology.

[31]  J. Elliott.  Cytokine upregulation in a murine model of familial amyotrophic lateral sclerosis. , 2001, Brain research. Molecular brain research.

[32]  Mark P Mattson,et al.  Alzheimer's Presenilin 1 Mutations Impair Kinesin-Based Axonal Transport , 2003, The Journal of Neuroscience.

[33]  Aldo Quattrone,et al.  Charcot-Marie-Tooth type 4B is caused by mutations in the gene encoding myotubularin-related protein-2 , 2000, Nature Genetics.

[34]  L. Greensmith,et al.  A mutation in dynein rescues axonal transport defects and extends the life span of ALS mice , 2005, The Journal of cell biology.

[35]  L. Bruijn,et al.  Aggregation and motor neuron toxicity of an ALS-linked SOD1 mutant independent from wild-type SOD1. , 1998, Science.

[36]  J. Kurtzke.  Risk factors in amyotrophic lateral sclerosis. , 1991, Advances in neurology.

[37]  P. Hedera,et al.  Mutations in a newly identified GTPase gene cause autosomal dominant hereditary spastic paraplegia , 2001, Nature Genetics.

[38]  P. Andersen,et al.  Overloading of Stable and Exclusion of Unstable Human Superoxide Dismutase-1 Variants in Mitochondria of Murine Amyotrophic Lateral Sclerosis Models , 2006, The Journal of Neuroscience.

[39]  F. Joó,et al.  Ultrastructural evidence for altered calcium in motor nerve terminals in amyotrophc lateral sclerosis , 1996, Annals of neurology.

[40]  L. Greensmith,et al.  Silencing mutant SOD1 using RNAi protects against neurodegeneration and extends survival in an ALS model , 2005, Nature Medicine.

[41]  P. Bork,et al.  SPG20 is mutated in Troyer syndrome, an hereditary spastic paraplegia , 2002, Nature Genetics.

[42]  Robert H. Brown,et al.  A novel locus for familial amyotrophic lateral sclerosis, on chromosome 18q. , 2002, American journal of human genetics.

[43]  J. Goldy,et al.  Mutation of a putative protein degradation gene LITAF/SIMPLE in Charcot-Marie-Tooth disease 1C , 2003, Neurology.

[44]  N. Hirokawa,et al.  Charcot-Marie-Tooth Disease Type 2A Caused by Mutation in a Microtubule Motor KIF1Bβ , 2001, Cell.

[45]  G. Kollias,et al.  Onset and Progression in Inherited ALS Determined by Motor Neurons and Microglia , 2006, Science.

[46]  P. Carmeliet,et al.  VEGF is a modifier of amyotrophic lateral sclerosis in mice and humans and protects motoneurons against ischemic death , 2003, Nature Genetics.

[47]  I. Fridovich,et al.  Amyotrophic lateral sclerosis: A proposed mechanism , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[48]  J. Trojanowski,et al.  Neurofilaments and Orthograde Transport Are Reduced in Ventral Root Axons of Transgenic Mice that Express Human SOD1 with a G93A Mutation , 1997, The Journal of cell biology.

[49]  Peter M Andersen,et al.  Systematically perturbed folding patterns of amyotrophic lateral sclerosis (ALS)-associated SOD1 mutants. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[50]  O. Evgrafov,et al.  A new variant of Charcot-Marie-Tooth disease type 2 is probably the result of a mutation in the neurofilament-light gene. , 2000, American journal of human genetics.

[51]  P. Bergh,et al.  Heterozygous missense mutations in BSCL2 are associated with distal hereditary motor neuropathy and Silver syndrome , 2004, Nature Genetics.

[52]  D. Borchelt,et al.  Copper-binding-site-null SOD1 causes ALS in transgenic mice: aggregates of non-native SOD1 delineate a common feature. , 2003, Human molecular genetics.

[53]  K. Narasimhan.  Signaling myopia , 1999, Nature Neuroscience.

[54]  A. Bush.  Is ALS caused by an altered oxidative activity of mutant superoxide dismutase? , 2002, Nature Neuroscience.

[55]  Robert W. Taylor,et al.  Mitochondrial dysfunction in a cell culture model of familial amyotrophic lateral sclerosis. , 2002, Brain : a journal of neurology.

[56]  S. Sasaki,et al.  Impairment of fast axonal transport in the proximal axons of anterior horn neurons in amyotrophic lateral sclerosis , 1996, Neurology.

[57]  A. Levey,et al.  Selective loss of glial glutamate transporter GLT‐1 in amyotrophic lateral sclerosis , 1995, Annals of neurology.

[58]  Lin Jin,et al.  Aberrant RNA Processing in a Neurodegenerative Disease: the Cause for Absent EAAT2, a Glutamate Transporter, in Amyotrophic Lateral Sclerosis , 1998, Neuron.

[59]  Robert H. Brown,et al.  Mice deficient in the Rab5 guanine nucleotide exchange factor ALS2/alsin exhibit age-dependent neurological deficits and altered endosome trafficking. , 2006, Human molecular genetics.

[60]  N. Mazarakis,et al.  Therapeutic gene silencing in neurological disorders, using interfering RNA , 2005, Journal of Molecular Medicine.

[61]  D. Borchelt,et al.  High Molecular Weight Complexes of Mutant Superoxide Dismutase 1: Age-Dependent and Tissue-Specific Accumulation , 2002, Neurobiology of Disease.

[62]  S M Leber,et al.  Periaxin mutations cause recessive Dejerine-Sottas neuropathy. , 2001, American journal of human genetics.

[63]  J. Slade,et al.  Familial amyotrophic lateral sclerosis with a mutation in exon 4 of the Cu/Zn superoxide dismutase gene: pathological and immunocytochemical changes , 1996, Acta Neuropathologica.

[64]  V. La Bella,et al.  The role of calcium‐binding proteins in selective motoneuron vulnerability in amyotrophic lateral sclerosis , 1994, Annals of neurology.

[65]  W. Robberecht,et al.  Mutant small heat-shock protein 27 causes axonal Charcot-Marie-Tooth disease and distal hereditary motor neuropathy , 2004, Nature Genetics.

[66]  J. Rothstein,et al.  Focal loss of the glutamate transporter EAAT2 in a transgenic rat model of SOD1 mutant-mediated amyotrophic lateral sclerosis (ALS) , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[67]  J. Busciglio,et al.  Fast axonal transport misregulation and Alzheimer’s Disease , 2002, NeuroMolecular Medicine.

[68]  John Mitchell,et al.  A new familial amyotrophic lateral sclerosis locus on chromosome 16q12.1-16q12.2. , 2003, American journal of human genetics.

[69]  Robert H. Brown,et al.  SOD1 mutants linked to amyotrophic lateral sclerosis selectively inactivate a glial glutamate transporter , 1999, Nature Neuroscience.

[70]  P. Stieg,et al.  Functional role of caspase-1 and caspase-3 in an ALS transgenic mouse model. , 2000, Science.

[71]  C. Guégan,et al.  Programmed cell death in amyotrophic lateral sclerosis. , 2003, The Journal of clinical investigation.

[72]  G. Rosoklija,et al.  Recruitment of the Mitochondrial-Dependent Apoptotic Pathway in Amyotrophic Lateral Sclerosis , 2001, The Journal of Neuroscience.

[73]  S. Petri,et al.  Neural mitochondrial Ca2+ capacity impairment precedes the onset of motor symptoms in G93A Cu/Zn‐superoxide dismutase mutant mice , 2006, Journal of neurochemistry.

[74]  Shuh Narumiya,et al.  ALS2, a novel guanine nucleotide exchange factor for the small GTPase Rab5, is implicated in endosomal dynamics. , 2003, Human molecular genetics.

[75]  M. Pericak-Vance,et al.  A kinesin heavy chain (KIF5A) mutation in hereditary spastic paraplegia (SPG10). , 2002, American journal of human genetics.

[76]  G. McKhann,et al.  Spinal cord endoplasmic reticulum stress associated with a microsomal accumulation of mutant superoxide dismutase-1 in an ALS model. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[77]  R. Nixon,et al.  Defective Neurofilament Transport in Mouse Models of Amyotrophic Lateral Sclerosis: A Review , 2003, Neurochemical Research.

[78]  P. Andersen,et al.  Disulphide-reduced superoxide dismutase-1 in CNS of transgenic amyotrophic lateral sclerosis models. , 2006, Brain : a journal of neurology.

[79]  M. Beal,et al.  Motor neurons in Cu/Zn superoxide dismutase-deficient mice develop normally but exhibit enhanced cell death after axonal injury , 1996, Nature Genetics.

[80]  H. Hartung,et al.  Mutations in the small GTP-ase late endosomal protein RAB7 cause Charcot-Marie-Tooth type 2B neuropathy. , 2003, American journal of human genetics.

[81]  V. Silani,et al.  Early vacuolization and mitochondrial damage in motor neurons of FALS mice are not associated with apoptosis or with changes in cytochrome oxidase histochemical reactivity , 2001, Journal of the Neurological Sciences.

[82]  D. Kastner,et al.  Haplotypes and DNA sequence variation within and surrounding the transthyretin gene: genotype–phenotype correlations in familial amyloid polyneuropathy (V30M) in Portugal and Sweden , 2004, European Journal of Human Genetics.

[83]  T. Gillingwater,et al.  A mutation in the vesicle-trafficking protein VAPB causes late-onset spinal muscular atrophy and amyotrophic lateral sclerosis. , 2004, American journal of human genetics.

[84]  D. Price,et al.  Elevated free nitrotyrosine levels, but not protein-bound nitrotyrosine or hydroxyl radicals, throughout amyotrophic lateral sclerosis (ALS)-like disease implicate tyrosine nitration as an aberrant in vivo property of one familial ALS-linked superoxide dismutase 1 mutant. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[85]  M. Lupi,et al.  Neurodegeneration induced by complex I inhibition in a cellular model of familial amyotrophic lateral sclerosis , 2006, Brain Research Bulletin.

[86]  J. Haines,et al.  Mutations in Cu/Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis , 1993, Nature.

[87]  J. McCord.  Mutant mice, Cu,Zn superoxide dismutase, and motor neuron degeneration. , 1994, Science.

[88]  Timothy A. Miller,et al.  Virus‐delivered small RNA silencing sustains strength in amyotrophic lateral sclerosis , 2005, Annals of neurology.

[89]  L. Sandkuyl,et al.  Tissue-specific splicing mutation in acute intermittent porphyria. , 1989, Proceedings of the National Academy of Sciences of the United States of America.

[90]  J. Bouchard,et al.  Erratum: The K-Cl cotransporter KCC3 is mutant in a severe peripheral neuropathy associated with agenesis of the corpus callosum (Nature Genetics (2002) 32(384-392)) , 2002 .

[91]  J. Coyle,et al.  Abnormal excitatory amino acid metabolism in amyotrophic lateral sclerosis , 1990, Annals of neurology.

[92]  Carsten Bergmann,et al.  Mutation of the SBF2 gene, encoding a novel member of the myotubularin family, in Charcot-Marie-Tooth neuropathy type 4B2/11p15. , 2003, Human molecular genetics.

[93]  D. W. Mulder.  Clinical limits of amyotrophic lateral sclerosis. , 1982, Advances in neurology.

[94]  Massimo Zeviani,et al.  Cytochrome c Oxidase subunit I microdeletion in a patient with motor neuron disease , 1998, Annals of neurology.

[95]  Yasushi Hiraoka,et al.  Mutations in Dynein Link Motor Neuron Degeneration to Defects in Retrograde Transport , 2003, Science.

[96]  S. Locke.  Clinical Neurology , 1953, Progress in neurology and psychiatry.

[97]  A. Ludolph,et al.  A dynein mutation attenuates motor neuron degeneration in SOD1G93A mice , 2006, Experimental Neurology.

[98]  H. Hartung,et al.  Mutations in the small GTP-ase late endosomal protein RAB7 cause Charcot-Marie-Tooth type 2B neuropathy. , 2003, American journal of human genetics.

[99]  K. Fischbeck,et al.  Glycyl tRNA synthetase mutations in Charcot-Marie-Tooth disease type 2D and distal spinal muscular atrophy type V. , 2003, American journal of human genetics.

[100]  A. Dürr,et al.  Hereditary spastic paraplegia SPG13 is associated with a mutation in the gene encoding the mitochondrial chaperonin Hsp60. , 2002, American journal of human genetics.

[101]  M. Beal,et al.  Mutated Human SOD1 Causes Dysfunction of Oxidative Phosphorylation in Mitochondria of Transgenic Mice* , 2002, The Journal of Biological Chemistry.

[102]  L. Bruijn,et al.  Therapeutic targets for amyotrophic lateral sclerosis: current treatments and prospects for more effective therapies , 2006, Expert review of neurotherapeutics.

[103]  D. Borchelt,et al.  Coincident thresholds of mutant protein for paralytic disease and protein aggregation caused by restrictively expressed superoxide dismutase cDNA , 2005, Neurobiology of Disease.

[104]  D. Bredesen,et al.  Altered Reactivity of Superoxide Dismutase in Familial Amyotrophic Lateral Sclerosis , 1996, Science.

[105]  A. Al-Chalabi,et al.  Detection of serum reverse transcriptase activity in patients with ALS and unaffected blood relatives , 2005, Neurology.

[106]  J. Haines,et al.  Linkage of familial amyotrophic lateral sclerosis with frontotemporal dementia to chromosome 9q21-q22. , 2000, JAMA.

[107]  Ole Gredal,et al.  Toxicity of Familial ALS-Linked SOD1 Mutants from Selective Recruitment to Spinal Mitochondria , 2004, Neuron.

[108]  J. Kong,et al.  Massive Mitochondrial Degeneration in Motor Neurons Triggers the Onset of Amyotrophic Lateral Sclerosis in Mice Expressing a Mutant SOD1 , 1998, The Journal of Neuroscience.

[109]  E. Fisher,et al.  An integrated genetic, radiation hybrid, physical and transcription map of a region of distal mouse chromosome 12, including an imprinted locus and the 'Legs at odd angles' (Loa) mutation. , 2002, Gene.

[110]  E. Seeberg,et al.  Mutant Huntingtin Impairs Axonal Trafficking in Mammalian Neurons In Vivo and In Vitro , 2004, Molecular and Cellular Biology.

[111]  J. Thevelein,et al.  Disrupted function and axonal distribution of mutant tyrosyl-tRNA synthetase in dominant intermediate Charcot-Marie-Tooth neuropathy , 2006, Nature Genetics.

[112]  H. Horvitz,et al.  Identification of three novel mutations in the gene for Cu Zn superoxide dismutase in patients with familial amyotrophic lateral sclerosis , 1995, Neuromuscular Disorders.

[113]  J. Bouchard,et al.  The K–Cl cotransporter KCC3 is mutant in a severe peripheral neuropathy associated with agenesis of the corpus callosum , 2002, Nature Genetics.

[114]  J. Slade,et al.  Novel insertion in the KSP region of the neurofilament heavy gene in amyotrophic lateral sclerosis (ALS) , 1998, Neuroreport.

[115]  C. Andres,et al.  Abnormal SMN1 gene copy number is a susceptibility factor for amyotrophic lateral sclerosis , 2002, Annals of neurology.

[116]  H. Moser,et al.  Familial spastic paraparesis , 1985, Neurology.

[117]  J. Piette,et al.  Tangier disease is caused by mutations in the gene encoding ATP-binding cassette transporter 1 , 1999, Nature Genetics.

[118]  K. Abe,et al.  Ultrastructural study of mitochondria in the spinal cord of transgenic mice with a G93A mutant SOD1 gene , 2004, Acta Neuropathologica.

[119]  G. Sobue,et al.  Mitochondrial Localization of Mutant Superoxide Dismutase 1 Triggers Caspase-dependent Cell Death in a Cellular Model of Familial Amyotrophic Lateral Sclerosis* , 2002, The Journal of Biological Chemistry.

[120]  K. Domschke,et al.  Giant axonal neuropathy (GAN): Case report and two novel mutations in the gigaxonin gene , 2002, Neurology.

[121]  A. Munnich,et al.  X–linked spastic paraplegia and Pelizaeus–Merzbacher disease are allelic disorders at the proteolipid protein locus , 1994, Nature Genetics.

[122]  D. Cleveland,et al.  Caspase-1 and -3 are sequentially activated in motor neuron death in Cu,Zn superoxide dismutase-mediated familial amyotrophic lateral sclerosis. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[123]  M. Cudkowicz,et al.  Limited corticospinal tract involvement in amyotrophic lateral sclerosis subjects with the A4V mutation in the copper/zinc superoxide dismutase gene , 1998, Annals of neurology.

[124]  H. Cross,et al.  Maspardin is mutated in mast syndrome, a complicated form of hereditary spastic paraplegia associated with dementia. , 2003, American journal of human genetics.

[125]  M. Kavanaugh,et al.  Excitatory amino acid transporter 5, a retinal glutamate transporter coupled to a chloride conductance. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[126]  R. Stevenson,et al.  X–linked spastic paraplegia (SPG1), MASA syndrome and X–linked hydrocephalus result from mutations in the L1 gene , 1994, Nature Genetics.

[127]  W. Snider,et al.  Restricted Expression of G86R Cu/Zn Superoxide Dismutase in Astrocytes Results in Astrocytosis But Does Not Cause Motoneuron Degeneration , 2000, The Journal of Neuroscience.

[128]  D. Borchelt,et al.  Mutations associated with amyotrophic lateral sclerosis convert superoxide dismutase from an antiapoptotic gene to a proapoptotic gene: studies in yeast and neural cells. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[129]  P. Ince,et al.  Calcium‐permeable α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazole propionic acid receptors: A molecular determinant of selective vulnerability in amyotrophic lateral sclerosis , 1997 .

[130]  J. Rothstein,et al.  Decreased glutamate transport by the brain and spinal cord in amyotrophic lateral sclerosis. , 1992, The New England journal of medicine.

[131]  K. Hensley,et al.  Journal of Neuroinflammation Primary Glia Expressing the G93a-sod1 Mutation Present a Neuroinflammatory Phenotype and Provide a Cellular System for Studies of Glial Inflammation , 2022 .

[132]  Impaired retrograde axonal transport of adenovirus-mediated E. coli LacZ gene in the mice carrying mutant SOD1 gene , 2001, Neuroscience Letters.

[133]  T. Wienker,et al.  Mutations in the gene encoding immunoglobulin μ-binding protein 2 cause spinal muscular atrophy with respiratory distress type 1 , 2001, Nature Genetics.

[134]  R. Kalb,et al.  Mutant superoxide dismutase disrupts cytoplasmic dynein in motor neurons , 2005, Neuroreport.

[135]  D. Howland,et al.  Disruption of Dynein/Dynactin Inhibits Axonal Transport in Motor Neurons Causing Late-Onset Progressive Degeneration , 2002, Neuron.

[136]  C. Wijmenga,et al.  Lack of association between VEGF polymorphisms and ALS in a Dutch population , 2005, Neurology.

[137]  K. Abe,et al.  Impairment of axonal transport in the axon hillock and the initial segment of anterior horn neurons in transgenic mice with a G93A mutant SOD1 gene , 2005, Acta Neuropathologica.

[138]  B. Pettmann,et al.  Chronic activation in presymptomatic amyotrophic lateral sclerosis (ALS) mice of a feedback loop involving Fas, Daxx, and FasL. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[139]  H. Horvitz,et al.  A locus on chromosome 9p confers susceptibility to ALS and frontotemporal dementia , 2006, Neurology.

[140]  A. Afifi,et al.  Ultrastructure of atrophic muscle in amyotrophic lateral sclerosis , 1966, Neurology.

[141]  Shin J. Oh,et al.  Mutant dynactin in motor neuron disease , 2003, Nature Genetics.

[142]  M Nakagawa,et al.  Rapid disease progression correlates with instability of mutant SOD1 in familial ALS , 2005, Neurology.

[143]  M. Dubois‐Dauphin,et al.  Delaying Caspase Activation by Bcl-2: A Clue to Disease Retardation in a Transgenic Mouse Model of Amyotrophic Lateral Sclerosis , 2000, The Journal of Neuroscience.

[144]  N. Laing,et al.  Toxic mutants in Charcot's sclerosis , 1995, Nature.

[145]  C. Henderson,et al.  Lentiviral-mediated silencing of SOD1 through RNA interference retards disease onset and progression in a mouse model of ALS , 2005, Nature Medicine.

[146]  J. Wadiche,et al.  Functional comparisons of three glutamate transporter subtypes cloned from human motor cortex , 1994, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[147]  F. Menzies,et al.  Mitochondrial involvement in amyotrophic lateral sclerosis , 2002, Neurochemistry International.

[148]  V. Timmerman,et al.  Molecular genetics of distal hereditary motor neuropathies. , 2004, Human molecular genetics.

[149]  D. Cleveland,et al.  Determinants of rapid disease progression in ALS , 2005, Neurology.

[150]  M. Kavanaugh,et al.  An excitatory amino-acid transporter with properties of a ligand-gated chloride channel , 1995, Nature.

[151]  Zuoshang Xu,et al.  Mutant Cu, Zn Superoxide Dismutase that Causes Motoneuron Degeneration Is Present in Mitochondria in the CNS , 2002, The Journal of Neuroscience.

[152]  Zuoshang Xu,et al.  Mitochondrial electron transport chain complex dysfunction in a transgenic mouse model for amyotrophic lateral sclerosis , 2002, Journal of neurochemistry.

[153]  T. Koepsell,et al.  Incidence of amyotrophic lateral sclerosis in three counties in western Washington state , 1996, Neurology.

[154]  Robert H. Brown,et al.  RNA interference-mediated silencing of mutant superoxide dismutase rescues cyclosporin A-induced death in cultured neuroblastoma cells. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[155]  Betty Y. S. Kim,et al.  Minocycline inhibits cytochrome c release and delays progression of amyotrophic lateral sclerosis in mice , 2002, Nature.

[156]  S. Appel,et al.  Immune reactivity in a mouse model of familial ALS correlates with disease progression , 2001, Neurology.

[157]  Robert H. Brown,et al.  Sixteen novel mutations in the Cu/Zn superoxide dismutase gene in amyotrophic lateral sclerosis: a decade of discoveries, defects and disputes. , 2003, Amyotrophic lateral sclerosis and other motor neuron disorders : official publication of the World Federation of Neurology, Research Group on Motor Neuron Diseases.

[158]  K. Fischbeck,et al.  Androgen receptor gene mutations in X-linked spinal and bulbar muscular atrophy , 1991, Nature.

[159]  J. Weissenbach,et al.  Identification and characterization of a spinal muscular atrophy-determining gene , 1995, Cell.

[160]  M. Gurney,et al.  Formation of high molecular weight complexes of mutant Cu, Zn-superoxide dismutase in a mouse model for familial amyotrophic lateral sclerosis. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[161]  A. F. Soleng,et al.  A thorny question: how does activity maintain dendritic spines? , 1999, Nature Neuroscience.

[162]  C. Stewart,et al.  Homozygous defects in LMNA, encoding lamin A/C nuclear-envelope proteins, cause autosomal recessive axonal neuropathy in human (Charcot-Marie-Tooth disorder type 2) and mouse. , 2002, American journal of human genetics.

[163]  J S Beckman,et al.  Induction of nitric oxide-dependent apoptosis in motor neurons by zinc-deficient superoxide dismutase. , 1999, Science.

[164]  Holger Hummerich,et al.  Mutations in the endosomal ESCRTIII-complex subunit CHMP2B in frontotemporal dementia , 2005, Nature Genetics.

[165]  K. Fischbeck,et al.  Connexin mutations in X-linked Charcot-Marie-Tooth disease. , 1993, Science.

[166]  Minh N. H. Nguyen,et al.  Wild-Type Nonneuronal Cells Extend Survival of SOD1 Mutant Motor Neurons in ALS Mice , 2003, Science.

[167]  F. Baas,et al.  Homozygous deletion of the survival motor neuron 2 gene is a prognostic factor in sporadic ALS , 2001, Neurology.

[168]  R. Morimoto,et al.  Huntingtin and Mutant SOD1 Form Aggregate Structures with Distinct Molecular Properties in Human Cells* , 2006, Journal of Biological Chemistry.

[169]  M. Gurney,et al.  Protein Oxidative Damage in a Transgenic Mouse Model of Familial Amyotrophic Lateral Sclerosis , 1998, Journal of neurochemistry.

[170]  D. Styne.  The Regulation of Pubertal Growth , 2003, Hormone Research in Paediatrics.

[171]  A. Fluharty,et al.  Metachromatic leukodystrophy caused by a partial cerebroside sulfatase defect , 1982, Clinical genetics.

[172]  F. Gage,et al.  Retrograde Viral Delivery of IGF-1 Prolongs Survival in a Mouse ALS Model , 2003, Science.

[173]  B. Trapp,et al.  The neuroprotective factor Wlds does not attenuate mutant SOD1-mediated motor neuron disease , 2007, NeuroMolecular Medicine.

[174]  Kurtzke Jf.  Risk factors in amyotrophic lateral sclerosis. , 1991 .

[175]  S. Züchner,et al.  Mutations in a gene encoding a novel SH3/TPR domain protein cause autosomal recessive Charcot-Marie-Tooth type 4C neuropathy. , 2003, American journal of human genetics.

[176]  W. Kunz,et al.  Impairment of mitochondrial function in skeletal muscle of patients with amyotrophic lateral sclerosis , 1998, Journal of the Neurological Sciences.

[177]  D. Borchelt,et al.  Caspase-1 is activated in neural cells and tissue with amyotrophic lateral sclerosis-associated mutations in copper-zinc superoxide dismutase. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[178]  E. Bertini,et al.  Unstable mutants in the peripheral endosomal membrane component ALS2 cause early-onset motor neuron disease , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[179]  A. Pramatarova,et al.  Neuron-Specific Expression of Mutant Superoxide Dismutase 1 in Transgenic Mice Does Not Lead to Motor Impairment , 2001, The Journal of Neuroscience.

[180]  G. Másson,et al.  A new mutation of the lamin A/C gene leading to autosomal dominant axonal neuropathy, muscular dystrophy, cardiac disease, and leuconychia , 2004, Journal of Medical Genetics.

[181]  J. Gilbert,et al.  Ganglioside-induced differentiation-associated protein-1 is mutant in Charcot-Marie-Tooth disease type 4A/8q21 , 2002, Nature Genetics.

[182]  Ole A. Andreassen,et al.  Neuroprotective effects of creatine in a transgenic animal model of amyotrophic lateral sclerosis , 1999, Nature Medicine.

[183]  P. Andersen,et al.  Autosomal recessive adult-onset amyotrophic lateral sclerosis associated with homozygosity for Asp90Ala CuZn-superoxide dismutase mutation. A clinical and genealogical study of 36 patients. , 1996, Brain : a journal of neurology.

[184]  B. Monia,et al.  Antisense oligonucleotide therapy for neurodegenerative disease. , 2006, The Journal of clinical investigation.

[185]  F. Baas,et al.  N-myc downstream-regulated gene 1 is mutated in hereditary motor and sensory neuropathy-Lom. , 2000, American journal of human genetics.

[186]  J. Holstege,et al.  Human Cu/Zn Superoxide Dismutase (SOD1) Overexpression in Mice Causes Mitochondrial Vacuolization, Axonal Degeneration, and Premature Motoneuron Death and Accelerates Motoneuron Disease in Mice Expressing a Familial Amyotrophic Lateral Sclerosis Mutant SOD1 , 2000, Neurobiology of Disease.

[187]  Noah W. Gray,et al.  Alsin Is a Rab5 and Rac1 Guanine Nucleotide Exchange Factor* , 2004, Journal of Biological Chemistry.

[188]  H. Tonoki,et al.  Mutations in the TRKA/NGF receptor gene in patients with congenital insensitivity to pain with anhidrosis , 1996, Nature Genetics.

[189]  G. Rosoklija,et al.  Increased expression of the pro‐inflammatory enzyme cyclooxygenase‐2 in amyotrophic lateral sclerosis , 2001, Annals of neurology.

[190]  John W Griffin,et al.  DNA/RNA helicase gene mutations in a form of juvenile amyotrophic lateral sclerosis (ALS4). , 2004, American journal of human genetics.

[191]  S. Minotti,et al.  Mutant Cu/Zn-Superoxide Dismutase Proteins Have Altered Solubility and Interact with Heat Shock/Stress Proteins in Models of Amyotrophic Lateral Sclerosis* , 2001, The Journal of Biological Chemistry.

[192]  P. Watkins,et al.  Identification of PAHX, a Refsum disease gene , 1997, Nature Genetics.

[193]  I. Glass,et al.  Senataxin, the yeast Sen1p orthologue: Characterization of a unique protein in which recessive mutations cause ataxia and dominant mutations cause motor neuron disease , 2006, Neurobiology of Disease.

[194]  T. Shows,et al.  Fine assignment of beta-hexosaminidase A alpha-subunit on 15q23-q24 by high resolution in situ hybridization. , 1990, The Tohoku journal of experimental medicine.

[195]  D L Price,et al.  Copper chaperone for superoxide dismutase is essential to activate mammalian Cu/Zn superoxide dismutase. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[196]  M. Pericak-Vance,et al.  Linkage of a commoner form of recessive amyotrophic lateral sclerosis to chromosome 15q15-q22 markers , 1998, Neurogenetics.

[197]  Robert H. Brown,et al.  Amyotrophic Lateral Sclerosis-linked Glutamate Transporter Mutant Has Impaired Glutamate Clearance Capacity* , 2001, The Journal of Biological Chemistry.

[198]  B. Crain,et al.  Linkage of the gene for an autosomal dominant form of juvenile amyotrophic lateral sclerosis to chromosome 9q34. , 1998, American journal of human genetics.

[199]  M. Koenig,et al.  The gene encoding gigaxonin, a new member of the cytoskeletal BTB/kelch repeat family, is mutated in giant axonal neuropathy , 2000, Nature Genetics.

[200]  A. Sik,et al.  Chromogranin-mediated secretion of mutant superoxide dismutase proteins linked to amyotrophic lateral sclerosis , 2006, Nature Neuroscience.

[201]  H. Horvitz,et al.  Mutations in the glutamate transporter EAAT2 gene do not cause abnormal EAAT2 transcripts in amyotrophic lateral sclerosis , 1998, Annals of neurology.

[202]  Danqing Zhu,et al.  Mutations in the pleckstrin homology domain of dynamin 2 cause dominant intermediate Charcot-Marie-Tooth disease , 2005, Nature Genetics.

[203]  D. Borchelt,et al.  Axonal Transport of Mutant Superoxide Dismutase 1 and Focal Axonal Abnormalities in the Proximal Axons of Transgenic Mice , 1998, Neurobiology of Disease.

[204]  M. Pericak-Vance,et al.  Mutations in the mitochondrial GTPase mitofusin 2 cause Charcot-Marie-Tooth neuropathy type 2A , 2004, Nature Genetics.

[205]  M. Gurney,et al.  Relationship of oxygen radical‐induced lipid peroxidative damage to disease onset and progression in a transgenic model of familial ALS , 1998, Journal of neuroscience research.

[206]  M. Dubois‐Dauphin,et al.  Bax and Bcl‐2 Interaction in a Transgenic Mouse Model of Familial Amyotrophic Lateral Sclerosis , 1999, Journal of neurochemistry.

[207]  I. Reynolds,et al.  Mitochondrial Depolarization in Glutamate-Stimulated Neurons: An Early Signal Specific to Excitotoxin Exposure , 1996, The Journal of Neuroscience.

[208]  M. Carson,et al.  ALS, SOD and peroxynitrite , 1993, Nature.

[209]  Mulder Dw.  Clinical limits of amyotrophic lateral sclerosis. , 1982 .

[210]  T. Atsumi.  The ultrastructure of intramuscular nerves in amyotrophic lateral sclerosis , 2004, Acta Neuropathologica.

[211]  Robert H. Brown,et al.  Amyotrophic Lateral Sclerosis-Associated SOD1 Mutant Proteins Bind and Aggregate with Bcl-2 in Spinal Cord Mitochondria , 2004, Neuron.

[212]  A. Lengeling,et al.  Mutation of Vps54 causes motor neuron disease and defective spermiogenesis in the wobbler mouse , 2005, Nature Genetics.

[213]  F. Baas,et al.  De-novo mutation in hereditary motor and sensory neuropathy type I , 1992, The Lancet.

[214]  Jeffrey D. Rothstein,et al.  From charcot to lou gehrig: deciphering selective motor neuron death in als , 2001, Nature Reviews Neuroscience.

[215]  M. Pericak-Vance,et al.  Erratum: The gene encoding alsin, a protein with three guanine-nucleotide exchange factor domains, is mutated in a form of recessive amyotrophic lateral sclerosis (Nature Genetics (2001) 29 (160-165)) , 2001 .

[216]  C. Lewis,et al.  Two families with familial amyotrophic lateral sclerosis are linked to a novel locus on chromosome 16q. , 2003, American journal of human genetics.