Complex Genetics of Amyotrophic Lateral Sclerosis

Abstract

Amyotrophic lateral sclerosis (ALS) is a common adult-onset neurodegenerative disease leading to paralysis and death typically within 2–5 years of diagnosis. Approximately 10% of ALS cases are inherited, with the remainder of cases being sporadic in origin. This distribution of familial and sporadic disease is similar to other adult-onset neurodegenerative diseases, such as Parkinson disease and Alzheimer disease (see, e.g., Przedborski et al. Przedborski et al., 2003Przedborski S Vila M Jackson-Lewis V Series introduction: neurodegeneration: what is it and where are we?.J Clin Invest. 2003; 111: 3-10Crossref PubMed Scopus (50) Google Scholar). The annual incidence of ALS is 1–2 per 100,000, leading to a lifetime risk of developing ALS of 1 per 800 (Cleveland and Rothstein Cleveland and Rothstein, 2001Cleveland DW Rothstein JD From Charcot to Lou Gehrig: deciphering selective motor neuron death in ALS.Nat Rev Neurosci. 2001; 2: 806-819Crossref PubMed Scopus (759) Google Scholar). Except for atypical variants of ALS, the familial form of disease is clinically indistinguishable from the sporadic cases (see, e.g., Hand and Rouleau Hand and Rouleau, 2002Hand CK Rouleau GA Familial amyotrophic lateral sclerosis.Muscle Nerve. 2002; 25: 135-159Crossref PubMed Scopus (105) Google Scholar). There is a slight male-to-female preponderance (1.3:1–1.6:1) that appears to be decreasing (Nelson Nelson, 1995Nelson LM Epidemiology of ALS.Clin Neurosci. 1995; 3: 327-331PubMed Google Scholar). Similarly, some epidemiologic studies suggest that the overall incidence of ALS is rising (Riggs and Schochet Riggs and Schochet, 1992Riggs JE Schochet Jr, SS Rising mortality due to Parkinson’s disease and amyotrophic lateral sclerosis: a manifestation of the competitive nature of human mortality.J Clin Epidemiol. 1992; 45: 1007-1012Abstract Full Text PDF PubMed Scopus (21) Google Scholar). Pathologic features of ALS include loss of motor neurons in the spinal ventral horns, most brainstem motor nuclei, and motor cortex. Interestingly, Onuf’s nucleus, which controls urethral and sphincter function, and motor neurons in the oculomotor, trochlear, and abducens cranial nerve nuclei are spared. Histopathological features include ubiquitinated inclusions in lower motor neurons and axonal swellings that are thought to contain disarrayed neurofilaments (Ince Ince, 2000Ince PG Neuropathology.in: Brown Jr, RH Meininger K Swash M Amyotrophic lateral sclerosis. Martin Dunitz, London2000: 83-112Google Scholar). It is thought that the process of ALS begins with an initiation or triggering event, followed by the propagation of motor neuron demise up and down the spinal cord (see Armon [Armon, 2003Armon C Epidemiology of amyotrophic lateral sclerosis/motor neuron disease.in: Shaw PJ Strong MJ Motor neuron disease (Blue Book). Butterworth-Heine mann, Philadelphia2003: 167-205Google Scholar] for a detailed description of this hypothesis). The exact mechanisms underlying the selective motor neuron degeneration in ALS remain elusive, but experimental evidence implicates many potential factors, including oxidative damage, excitotoxicity, apoptosis, abnormal neurofilament function, defects in axonal transport, aberrant protein processing and degradation, increased inflammation, and mitochondrial dysfunction (Cleveland and Rothstein Cleveland and Rothstein, 2001Cleveland DW Rothstein JD From Charcot to Lou Gehrig: deciphering selective motor neuron death in ALS.Nat Rev Neurosci. 2001; 2: 806-819Crossref PubMed Scopus (759) Google Scholar; Bruijn et al. Bruijn et al., 2004Bruijn LI Miller TM Cleveland DW Unraveling the mechanisms involved in motor neuron degeneration in ALS.Ann Rev Neurosci. 2004; 27: 723-749Crossref PubMed Scopus (763) Google Scholar). Although hypotheses abound, it is difficult to determine which of these processes is most important in triggering cell dysfunction and death and what determines the selective vulnerability of motor neurons. The World Federation of Neurology diagnostic criteria for ALS include the presence of upper and lower motor neuron degeneration with a progressive phenotype in the absence of evidence that indicates other diseases (Revised Criteria for the Diagnosis of ALS Web site). Typically, there is no cognitive impairment or loss of sensory nerve function, although there are ALS variants that include these symptoms. Upper motor neuron signs include clonus and hyperreflexia, and lower motor neuron signs include atrophy, weakness, and fasciculations. ALS diagnoses are categorized as “clinically definite,” “clinically probable,” and “clinically possible,” on the basis of the number and location of the cardinal signs. The diagnosis of ALS is often one of excluding other diseases and waiting for the disease to progress to meet the full diagnostic criteria. A variety of studies are often performed to exclude syndromes that have symptoms that mimic ALS, including postpoliomyelitis syndrome; multifocal motor neuropathy; endocrinopathies, especially hyperparathyroid or hyperthyroid states; lead intoxication; infections; and paraneoplastic syndromes (Motor Syndromes Web site; Revised Criteria for the Diagnosis of ALS Web site). There is an obvious genetic component in only ∼10% of ALS cases; these cases exhibit significant phenotypic and genetic heterogeneity. At least 12 genetic loci, with dominant, recessive, and X-linked patterns of inheritance, have been associated with familial ALS and related ALS syndromes (table 1). Although specific genetic alterations do not appear to cause sporadic ALS, a number of potential susceptibility and modifier loci have been identified (table 2). I will discuss the genes and loci that have been implicated in the causation and/or susceptibility of both sporadic and familial ALS.Table 1Familial ALS LociMIM NumberDiseaseType(s) of InheritanceDiseaseGeneGeneOnsetChromosomeIntervalSize (Mb)Reference(s)ALS1Dominant and recessive (D90A)105400147450SOD1Adult21q22.1Rosen et al. Rosen et al., 1993Rosen DR Siddique T Patterson D Figlewicz DA Sapp P Hentati A Donaldson D et al.Mutations in Cu/Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis.Nature. 1993; 362: 59-62Crossref PubMed Scopus (3049) Google Scholar; Al-Chalabi et al. Al-Chalabi et al., 1998Al-Chalabi A Andersen PM Chioza B Shaw C Sham PC Robberecht W Matthijs G Camu W Marklund SL Forsgren L Rouleau G Laing NG Hurse PV Siddique T Leigh PN Powell JF Recessive amyotrophic lateral sclerosis families with the D90A SOD1 mutation share a common founder: evidence for a linked protective factor.Hum Mol Genet. 1998; 7: 2045-2050Crossref PubMed Google ScholarALS2Recessive205100606352Alsin (ALS2)Juvenile2q33Hadano et al. Hadano et al., 2001Hadano S Hand CK Osuga H Yanagisawa Y Otomo A Devon RS Miyamoto N Showguchi-Miyata J Okada Y Singaraja R Figlewicz DA Kwiatkowski T Hosler BA Sagie T Skaug J Nasir J Brown Jr, RH Scherer SW Rouleau GA Hayden MR Ikeda JE A gene encoding a putative GTPase regulator is mutated in familial amyotrophic lateral sclerosis 2.Nat Genet. 2001; 29: 166-173Crossref PubMed Scopus (413) Google Scholar; Yang et al. Yang et al., 2001Yang Y Hentati A Deng HX Dabbagh O Sasaki T Hirano M Hung WY Ouahchi K Yan J Azim AC Cole N Gascon G Yagmour A Ben-Hamida M Pericak-Vance M Hentati F Siddique T The gene encoding alsin, a protein with three guanine-nucleotide exchange factor domains, is mutated in a form of recessive amyotrophic lateral sclerosis.Nat Genet. 2001; 29: 160-165Crossref PubMed Scopus (455) Google ScholarALS3Dominant606640Adult18q21D18S846–D18S11098Hand et al. Hand et al., 2002Hand CK Khoris J Salachas F Gros-Louis F Lopes AAS Mayeux-Portas V Brown Jr, RH Meininger V Camu W Rouleau GA A novel locus for familial amyotrophic lateral sclerosis on chromosome 18q.Am J Hum Genet. 2002; 70: 251-256Abstract Full Text Full Text PDF PubMed Scopus (85) Google Scholar; Sapp et al. Sapp et al., 2003Sapp PC Hosler BA McKenna-Yasek D Chin W Gann A Genise H Gorenstein J Huang M Sailer W Scheffler M Valesky M Haines JL Pericak-Vance M Siddique T Horvitz HR Brown Jr, RH Identification of two novel loci for dominantly inherited familial amyotrophic lateral sclerosis.Am J Hum Genet. 2003; 73: 397-403Abstract Full Text Full Text PDF PubMed Scopus (80) Google ScholarALS4Dominant602433608465SETXJuvenile9q34Chen et al. Chen et al., 2004Chen Y-Z Bennet CL Huynh HM Blair IP Puls I Irobi J Dierick I Abel A Kennerson ML Rabin BA Nicholson GA Auer-Grumbach M Wagner K De Jonghe P Griffin JW Fischbeck KH Timmerman V Cornblath DR Chance PF DNA/RNA helicase gene mutations in a form of juvenile amyotrophic lateral sclerosis (ALS4).Am J Hum Genet. 2004; 74: 1128-1135Abstract Full Text Full Text PDF PubMed Scopus (365) Google ScholarALS5Recessive602099Juvenile15q15.1-q21.1Hentati et al. 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Sapp et al., 2003Sapp PC Hosler BA McKenna-Yasek D Chin W Gann A Genise H Gorenstein J Huang M Sailer W Scheffler M Valesky M Haines JL Pericak-Vance M Siddique T Horvitz HR Brown Jr, RH Identification of two novel loci for dominantly inherited familial amyotrophic lateral sclerosis.Am J Hum Genet. 2003; 73: 397-403Abstract Full Text Full Text PDF PubMed Scopus (80) Google ScholarALS8Dominant608627605704VAPBAdult20q13.33Nishimura et al. 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Hosler et al., 2000Hosler BA Siddique T Sapp PC Sailor W Huang MC Hossain A Daube JR Nance M Fan C Kaplan J Hung W-Y McKenna-Yasek D Haines JL Pericak-Vance MA Horvitz HR Brown Jr, RH Linkage of familial amyotrophic lateral sclerosis with frontotemporal dementia to chromosome 9q21-q22.JAMA. 2000; 284: 1664-1669Crossref PubMed Google ScholarALS XDominantAdultXp11-q12Siddique et al. Siddique et al., 1998aSiddique T Hong ST Brooks BR Hung WY Siddique NA Rimmler J Kaplan JP Haines JL Brown Jr, RH Pericak-Vance MA X-linked dominant locus for late-onset familial amyotrophic lateral sclerosis.Am J Hum Genet Suppl. 1998a; 63: A308Google ScholarALS with dementia, ParkinsonismDominant600274157140MAPTAdult17q21Clark et al. 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Puls et al., 2003Puls I Jonnakuty C LaMonte BH Holzbaur EL Tokito M Mann E Floeter MK Bidus K Drayna D Oh SJ Brown Jr, RH Ludlow CL Fischbeck KH Mutant dynactin in motor neuron disease.Nat Genet. 2003; 33: 455-456Crossref PubMed Scopus (503) Google Scholar Open table in a new tab Table 2Human Susceptibility and Modifier LociGeneMIM NumberChromosomeVariantAssociationReferenceNEFH16223022q12.1-q13.1KSP deletionsSporadicAl-Chalabi et al. Al-Chalabi et al., 1999Al-Chalabi A Andersen PM Nilsson P Chioza B Andersson JL Russ C Shaw CE Powell JF Leigh PN Deletions of the heavy neurofilament subunit tail in amyotrophic lateral sclerosis.Hum Mol Genet. 1999; 8: 157-164Crossref PubMed Scopus (205) Google ScholarVEGF1922406p12Promoter SNPsSporadicLambrechts et al. Lambrechts et al., 2003Lambrechts D Storkebaum E Morimoto M Del-Favero J Desmet F Marklund SL Wyns S et al.VEGF is a modifier of amyotrophic lateral sclerosis in mice and humans and protects motoneurons against ischemic death.Nat Genet. 2003; 34: 383-394Crossref PubMed Scopus (531) Google ScholarSMN16003545q12.2-q13.3Copy numberSporadicCorcia et al. Corcia et al., 2002Corcia P Mayeux-Portas V Khoris J de Toffol B Autret A Muh JP Camu W Andres C French ALS Research GroupAbnormal SMN1 gene copy number is a susceptibility factor for amyotrophic lateral sclerosis.Ann Neurol. 2002; 51: 243-246Crossref PubMed Scopus (64) Google ScholarSMN26016275q12.2-q13.3Copy numberSporadicVeldink et al. Veldink et al., 2001Veldink JH van den Berg LH Cobben JM Stulp RP De Jong JM Vogels OJ Baas F Wokke JH Scheffer H Homozygous deletion of the survival motor neuron 2 gene is a prognostic factor in sporadic ALS.Neurology. 2001; 56: 749-752Crossref PubMed Google ScholarCNTF11894511q12.2Null alleleFamilialGiess et al. Giess et al., 2002Giess R Holtmann B Braga M Grimm T Muller-Myhsok B Toyka KV Sendtner M Early onset of severe familial amyotrophic lateral sclerosis with a SOD-1 mutation: potential impact of CNTF as a candidate modifier gene.Am J Hum Genet. 2002; 70: 1277-1286Abstract Full Text Full Text PDF PubMed Scopus (86) Google ScholarApoE ɛ410774119q13.2ɛ4 genotypeSporadicDrory et al. Drory et al., 2001Drory VE Birnbaum M Korczyn AD Chapman Association of APOE ɛ4 allele with survival in amyotrophic lateral sclerosis.J Neurol Sci. 2001; 190: 17-20Abstract Full Text Full Text PDF PubMed Google ScholarEAAT260030011p13-p12Decreased expressionFamilial, sporadicRothstein et al. Rothstein et al., 1995Rothstein JD Van Kammen M Levey AI Martin LJ Kuncl RW Selective loss of glial glutamate transporter GLT-1 in amyotrophic lateral sclerosis.Ann Neurol. 1995; 38: 73-84Crossref PubMed Scopus (829) Google ScholarGluR21382474q32-q33Altered RNA editingSporadicKawahara et al. Kawahara et al., 2004Kawahara Y Ito K Sun H Aizawa H Kanazawa I Kawk S RNA editing and the death of motor neurons: there is a glutamate-receptor defect in patients with amyotrophic lateral sclerosis.Nature. 2004; 427: 801Crossref PubMed Scopus (164) Google Scholar Open table in a new tab There are at least six dominantly inherited, adult-onset ALS genes (table 1); however, only the gene for ALS1 (MIM 105400)—copper-zinc superoxide dismutase (SOD1 [MIM 147450]), on chromosome 21q22.1—has been identified. Mutations in SOD1 account for ∼20% of familial ALS (Rosen et al. Rosen et al., 1993Rosen DR Siddique T Patterson D Figlewicz DA Sapp P Hentati A Donaldson D et al.Mutations in Cu/Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis.Nature. 1993; 362: 59-62Crossref PubMed Scopus (3049) Google Scholar). Identifying the genes causing the remaining 80% of familial ALS cases will be challenging, since many of the remaining loci appear to segregate in individual families. The first ALS-associated gene to be identified was the SOD1 gene, on human chromosome 21 (Rosen et al. Rosen et al., 1993Rosen DR Siddique T Patterson D Figlewicz DA Sapp P Hentati A Donaldson D et al.Mutations in Cu/Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis.Nature. 1993; 362: 59-62Crossref PubMed Scopus (3049) Google Scholar). SOD1 is a 153–amino acid protein, containing one copper and one zinc, that is predominantly located in the cytoplasm as a homodimer. SOD1 detoxifies superoxide, creating oxygen and hydrogen peroxide, which can then be cleared by catalase and glutathione peroxidase. Copper is required for SOD1 activity, whereas zinc is thought to stabilize the protein structure. To date, >100 unique mutations in SOD1 have been identified (Andersen et al. Andersen et al., 2003Andersen PM Sims KB Xin WW Kiely R O’Neill G Ravits J Pioro E Harati Y Brower RD Levine JS Heinicke HU Seltzer W Boss M Brown Jr, RH Sixteen novel mutations in the Cu/Zn superoxide dismutase gene in amyotrophic lateral sclerosis: a decade of discoveries, defects and disputes.Amyotroph Lateral Scler Other Motor Neuron Disord. 2003; 4: 62-73Crossref PubMed Google Scholar; alsod.org Web site). The majority of mutations in SOD1 are missense mutations, with a small percentage of deletion and insertion mutations that result in prematurely terminated SOD1 polypeptides. The expression of a mutant SOD1 polypeptide, with or without residual SOD1 activity, is necessary to cause the ALS phenotype, suggesting a dominant negative mechanism rather than one of haploinsufficiency. Even after >10 years of investigation, the exact mechanism of SOD1-mediated pathogenesis remains uncertain. There is considerable phenotypic variation in SOD1-mediated ALS, including age at onset and severity and rate of decline; however, this can only partly be explained by the spectrum of mutations. Because clinical variation occurs among patients of the same SOD1 genotype and members of the same family (Andersen et al. Andersen et al., 1997Andersen PM Nilsson P Keranen M-L Forsgren L Hagglund J Karlsborg M Ronnevi L-O Gredal O Marklunk SL Phenotypic heterogeneity in motor neuron disease patients with CuZn-superoxide dismutase mutations in Scandinavia.Brain. 1997; 120: 1723-1737Crossref PubMed Scopus (187) Google Scholar), it is apparent that the phenotype is modified by other genetic and/or environmental factors. One example is the D90A SOD1 mutation, which is recessive in some genetic backgrounds but dominant in others (Al-Chalabi et al. Al-Chalabi et al., 1998Al-Chalabi A Andersen PM Chioza B Shaw C Sham PC Robberecht W Matthijs G Camu W Marklund SL Forsgren L Rouleau G Laing NG Hurse PV Siddique T Leigh PN Powell JF Recessive amyotrophic lateral sclerosis families with the D90A SOD1 mutation share a common founder: evidence for a linked protective factor.Hum Mol Genet. 1998; 7: 2045-2050Crossref PubMed Google Scholar). The recessive D90A SOD1 mutations share a common founder haplotype, suggesting that there is a linked cis-acting protective factor that makes this mutation recessive in this specific genetic background (Parton et al. Parton et al., 2002Parton MJ Broom W Andersen PM Al-Chalabi A Nigel Leigh P Powell JF Shaw CE D90A SOD1 ALS ConsortiumD90A-SOD1 mediated amyotrophic lateral sclerosis: a single founder for all cases with evidence for a cis-acting disease modifier in the recessive haplotype.Hum Mutat. 2002; 20: 473Crossref PubMed Scopus (73) Google Scholar). Genetic background also affects other forms of SOD1-mediated ALS. Although it causes one of the most severe forms of the disease, with death typically occurring <18 mo after diagnosis, the penetrance of the A4V SOD1 mutation is only 91% (Cudkowicz et al. Cudkowicz et al., 1997Cudkowicz ME McKenna-Yasek D Sapp PE Chin W Geller B Hayden DL Schoenfeld DA Hosler BA Horvitz HR Brown RH Epidemiology of mutations in superoxide dismutase in amyotrophic lateral sclerosis.Ann Neurol. 1997; 41: 210-221Crossref PubMed Scopus (301) Google Scholar). Similarly, the A89V SOD1 mutation shows incomplete penetrance and variable age at onset (Rezania et al. Rezania et al., 2003Rezania K Yan J Dellefave L Deng H-X Siddique N Pascuzzi RT Siddique T Roos RP A rare Cu/Zn superoxide dismutase mutation causing familial amyotrophic lateral sclerosis with variable age of onset, incomplete penetrance and a sensory neuropathy.Amyotroph Lateral Scler Other Motor Neuron Disord. 2003; 4: 162-166Crossref PubMed Google Scholar). The variable penetrance and age at onset caused by SOD1 mutations can be mimicked in transgenic mouse models of ALS, by varying the mouse strain on which a mutation is carried (Kunst et al. Kunst et al., 2000Kunst C Messer L Gordon J Haines J Patterson D Genetic mapping of a mouse modifier gene that can prevent ALS onset.Genomics. 2000; 70: 181-189Crossref PubMed Scopus (44) Google Scholar). Transgenic mice that develop ALS-like phenotypes have been constructed with at least nine forms of mutant human SOD1: A4V, G93A, G85R, G37R, D90A, L126Z, H46R/H48Q, H46R/H48Q/H63G/H120G, and G127insTGGG (Dal Canto and Gurney Dal Canto and Gurney, 1995Dal Canto MC Gurney ME Neuropathological changes in two lines of mice carrying a transgene for mutant human Cu,Zn SOD, and in mice overexpressing wild type human SOD: a model of familial amyotrophic lateral sclerosis (FALS).Brain Res. 1995; 676: 25-40Crossref PubMed Scopus (283) Google Scholar; Wong et al. Wong et al., 1995Wong PC Pardo CA Borchelt DR Lee MK Copeland NG Jenkins NA Sisodia SS Cleveland DW Price DL An adverse property of a familial ALS-linked SOD1 mutation causes motor neuron disease characterized by vacuolar degeneration of mitochondria.Neuron. 1995; 14: 1105-1116Abstract Full Text PDF PubMed Google Scholar; Bruijn et al. Bruijn et al., 1997bBruijn LI Becher MW Lee MK Anderson KL Jenkins NA Copeland NG Sisodia SS Rothstein JD Borchelt DR Price DL Cleveland DW ALS-linked SOD1 mutant G85R mediates damage to astrocytes and promotes rapidly progressive disease with SOD1-containing inclusions.Neuron. 1997b; 18: 327-338Abstract Full Text Full Text PDF PubMed Scopus (763) Google Scholar; Brannstrom et al. Brannstrom et al., 1998Brannstrom T, Ernhill K, Marklund S, Nilsson P (1998) Transgenic mice homozygous for the Asp90Ala human SOD1 mutation develop ALS clinically and histologically. Paper presented at the Annual Meeting of the Society for Neuroscience, Los Angeles, November 7-12.Google Scholar; Deng et al. Deng et al., 1999Deng H-X Fu R Zhai H Siddique T A truncation mutation (L126Z) of SOD1 gene leads to ALS-like phenotype in transgenic mice.Am J Hum Genet Suppl. 1999; 65: A292Google Scholar; Wang et al. Wang et al., 2002Wang J Xu G Gonzales V Coonfield M Fromholt D Copeland NG Jenkins NA Borchelt DR Fibrillar inclusions and motor neuron degeneration in transgenic mice expressing superoxide dismutase 1 with a disrupted copper-binding site.Neurobiol Dis. 2002; 10: 128-138Crossref PubMed Scopus (145) Google Scholar, Wang et al., 2003Wang J Slunt H Gonzales V Fromholt D Coonfield M Copeland NG Jenkins NA Borchelt DR Copper-binding-site-null SOD1 causes ALS in transgenic mice: aggregates of non-native SOD1 delineate a common feature.Hum Mol Genet. 2003; 12: 2753-2764Crossref PubMed Scopus (172) Google Scholar; Jonsson et al. 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Nagai et al., 2001Nagai M Aoki M Miyoshi I Kato M Pasinelli P Kasai N Brown Jr, RH Itoyama Y Rats expressing human cytosolic copper-zinc superoxide dismutase transgenes with amyotrophic lateral sclerosis: associated mutations develop motor neuron disease.J Neurosci. 2001; 21: 9246-9254Crossref PubMed Google Scholar; Howland et al. Howland et al., 2002Howland DS Liu J She Y Goad B Maragakis NJ Kim B Erickson J Kulik J DeVito L Psaltis G DeGennaro LJ Cleveland DW Rothstein JD Focal loss of glutamate transporter EAAT2 in transgenic rat model of SOD1 mutant-mediated amyotrophic lateral sclerosis.Proc Natl Acad Sci USA. 2002; 99: 1604-1609Crossref PubMed Scopus (413) Google Scholar). Although each model of ALS is phenotypically consistent for a given mutation, they vary in their age at onset, disease progression, and certain histopathological features, mimicking the diversity of phenotypes observed in human ALS. In the mouse and rat models of ALS, the mutant SOD1 allele is expressed in the presence of the two endogenous copies of the wild-type SOD1 gene; thus, the mice and rats have either normal or increased SOD1 activity levels, depending on the activity of the SOD1 mutant expressed. However, SOD1 overexpression is not the cause of ALS, since mice overexpressing wild-type human SOD1 do not develop an ALS-like phenotype (Dal Canto and Gurney Dal Canto and Gurney, 1995Dal Canto MC Gurney ME Neuropathological changes in two lines of mice carrying a transgene for mutant human Cu,Zn SOD, and in mice overexpressing wild type human SOD: a model of familial amyotrophic lateral sclerosis (FALS).Brain Res. 1995; 676: 25-40Crossref PubMed Scopus (283) Google Scholar; Wong et al. Wong et al., 1995Wong PC Pardo CA Borchelt DR Lee MK Copeland NG Jenkins NA Sisodia SS Cleveland DW Price DL An adverse property of a familial ALS-linked SOD1 mutation causes motor neuron disease characterized by vacuolar degeneration of mitochondria.Neuron. 1995; 14: 1105-1116Abstract Full Text PDF PubMed Google Scholar). In G93A SOD1 mice (Jaarsma et al. Jaarsma et al., 2000Jaarsma D Haasdijk ED Grashorn JA Hawkins R van Duijn W Verspaget HW London J Holstege JC 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.Neurobiol Dis. 2000; 7: 623-643Crossref PubMed Scopus (181) Google Scholar) but not in G85R SOD1 mice (Bruijn et al. Bruijn et al., 1998Bruijn LI Houseweart MK Kato S Anderson KL Anderson SD Ohama E Reaume AG Scott RW Cleveland DW Aggregation and motor neuron toxicity of an ALS-linked SOD1 mutant independent from wild-type SOD1.Science. 1998; 281: 1851-1854Crossref PubMed Scopus (640) Google Scholar), overexpression of wild-type SOD1 accelerates disease onset and progression. Lack of SOD1 is also not sufficient to cause ALS in mice. Mice with SOD1 null alleles have a number of interesting phenotypes but do not develop symptoms of ALS (Reaume et al. Reaume et al., 1996Reaume AG Elliott JL Hoffman EK Kowall NW Ferrante RJ Siwek DF Wilcox HM Flood DG Beal MF Brown Jr, RH Scott RW Snider WD Motor neurons in Cu/Zn superoxide dismutase-deficient mice develop normally but exhibit enhanced cell death after axonal injury.Nat Genet. 1996; 13: 43-47Crossref PubMed Scopus (786) Google Scholar). Together, these results suggest that mutations in SOD1 cause a novel toxic gain of function that is lethal to motor neurons. Although ALS is predominantly a disease of motor neuron loss, neuronal expression of mutant SOD1 is not sufficient to cause ALS. Overexpression of mutant SOD1 in neurons or astrocytes alone does not cause ALS or motor neuron death in transgenic mice (Gong et al. Gong et al., 2000Gong YH Parsadanian AS Andreeva A Snider WD Elliott JL Restricted expression of G86R Cu/Zn superoxide dismutase in astrocytes results in astrocytosis but does not cause motoneuron degeneration.J Neurosci. 2000; 20: 660-665Crossref PubMed Google Scholar; Pramatarova et al. Pramatarova et al., 2001Pramatarova A Laganiere J Roussel J Brisebois K Rouleau GA Neuron-specific expression of mutant superoxide dismutase 1 in transgenic mice does not lead to motor impairment.J Neurosci. 2001; 21: 3369-3374Crossref PubMed Google Scholar; Lino et al. Lino et al., 2002Lino MM Schneider C Caroni P Accumulation of SOD1 mutants in postnatal motoneurons does not cause motoneuron pathology or motoneuron disease.J Neurosci. 2002; 22: 4825-4832Crossref PubMed Google Scholar). Studies in chimeric mice, created from mixtures of normal and mutant SOD1-expressing cells, reveal that toxicity to motor neurons requires damage from mutant SOD1 acting from within nonneuronal cells (Clement et al. Clement et al., 2003Clement AM Nguyen MD Roberts EA Garcia ML Boillee S Rule M McMahon AP Doucette W Siwek D Ferrante RJ Brown Jr, RH Julien JP Goldstein LS Cleveland DW Wild-type nonneuronal cells extend survival of