Nature Publishing Group

NEUROSCIENCE

 

 VOLUME 7 

|

 SEPTEMBER 2006 

|

 719

©

 

200

6

 

Nature Publishing Group

 

 

and a role for non-neuronal cells as modulators of neuron 

death. What other aspects are likely to be important in 

ALS? Looking ahead, we anticipate that several themes 

could emerge: disturbances of vesicular trafficking and 

axonal transport and further delineation of the ionic basis 

for excitotoxicity and the mechanisms whereby neurons 

and support cells compensate for this; more elaborate 

descriptions of the cellular defences against misfolded 

proteins; and, in SALS, approaches to detecting extrinsic 

causative factors (for example, infections and toxins). At 

present, it seems unlikely that the diverse hypotheses can 

be combined into a single explanation of ALS. Rather, it 

is likely that several seemingly disparate factors can trig-

ger motor neuron death as a final common pathway. If 

there are multiple pathways involved in motor neuron 

degeneration, there are also multiple targets for therapy. It 

is beyond the scope of this article to summarize the litera-

ture on therapeutic trials in human and rodent ALS (for a 

review, see 

REF. 179

). However, two lessons are emerging. 

First, the most effective therapies in ALS mice have deliv-

ered the beneficial agents directly to motor neurons. For 

example, insulin-like growth factor extended survival in 

the G93A-SOD1 mice when expressed from the type 2 

serotype of adeno-associated virus that, in turn, had been 

carried to the motor neuron by retrograde axonal trans-

port after intramuscular injection

180

. Second, spectacular 

benefits can be achieved with strategies that inactivate the 

mutant, disease-causing alleles

181,182

. The most compel-

ling approach to attenuating the diverse, often synergis-

tic downstream pathological processes is to shut off the 

production of the inciting, upstream protein, whether by 

RNA interference

181–185

, antisense oligonucleotides

186

 or 

some other method. Given contemporary advances in 

strategies to attenuate gene expression, it is striking that 

SOD1-mediated ALS, surely the most devastating form 

of this disease, affecting one-half of all adults in every 

affected family, might well be the first form of this hor-

rific disease to be treated successfully.

1.  

Mulder, D. W. Clinical limits of amyotrophic lateral 

sclerosis. Adv. Neurol. 36, 15–22 (1982).

2.  

McGuire, V., Longstreth, W. T. Jr, Koepsell, T. D. & 

van Belle, G. Incidence of amyotrophic lateral sclerosis 

in three counties in western Washington state. 

Neurology 47, 571–573 (1996).

3.  

Mitsumoto, H., Chad, D. A. & Pioro, E. P. Amyotrophic 

Lateral Sclerosis (Oxford Univ. Press, New York, 1998).

4.  

Kurtzke, J. K. L. in Clinical Neurology (ed. Joynt, R.) 

(Lippincott, Philadelphia, 1989).

5.  

Kurtzke, J. F. Risk factors in amyotrophic lateral 

sclerosis. Adv. Neurol. 56, 245–270 (1991).

6.  

Ince, P. G. in Amyotrophic Lateral Sclerosis (eds 

Brown, R. H. Jr, Meininger, V. & Swash, M.) 

83–112 (Martin Dunitz, London, 2000).

7.  

Cleveland, D. W. & Rothstein, J. D. From Charcot to 

Lou Gehrig: deciphering selective motor neuron death 

in ALS. Nature Rev. Neurosci. 2, 806–819 (2001).

8.  

Rowland, L. P. in Amyotrophic Lateral Sclerosis and 

Other Motor Neuron Diseases (ed. Rowland, L. P.) 

3–23 (Raven, 1992).

9.  

MacGowan, D. J., Scelsa, S. N. & Waldron, M. An ALS-

like syndrome with new HIV infection and complete 

response to antiretroviral therapy. Neurology 57, 

1094–1097 (2001).

10.   Steele, A. J. et al. Detection of serum reverse 

transcriptase activity in patients with ALS and 

unaffected blood relatives. Neurology 64, 454–458 

(2005).

11.   Rosen, D. R. et al. Mutations in Cu/Zn superoxide 

dismutase gene are associated with familial 

amyotrophic lateral sclerosis. Nature 362, 59–62 

(1993).

Describes the hallmark discovery that mutations 

in SOD1 cause ALS in a subset of familial cases.

12.   Yang, Y. et al. The gene encoding alsin, a protein 

with three guaninenucleotide exchange factor 

domains, is mutated in a form of recessive 

amyotrophic lateral sclerosis. Nature Genet. 29, 

160–165 (2001).

13.   Hadano, S. et al. A gene encoding a putative GTPase 

regulator is mutated in familial amyotrophic lateral 

sclerosis 2. Nature Genet. 29, 166–173 (2001).

14.   Chance, P. F. Linkage of the gene for an autosomal 

dominant form of juvenile amyotrophic lateral 

sclerosis to chromosome 9q34. Am. J. Hum. Genet. 

62, 633–640 (1998). 

15.   Chen, Y. Z. et al. DNA/RNA helicase gene mutations 

in a form of juvenile amyotrophic lateral sclerosis 

(ALS4). Am. J. Hum. Genet. 74, 1128–1135 

(2004).

16.   Nishimura, A. L. et al. A mutation in the vesicle-

trafficking protein VAPB causes late-onset spinal 

muscular atrophy and amyotrophic lateral sclerosis. 

Am. J. Hum. Genet. 75, 822–831 (2004).

17.   Puls, I. et al. Mutant dynactin in motor neuron 

disease. Nature Genet. 33, 455–456 (2003).

References 12–17 describe ALS-causing gene 

mutations.

18.   Ruddy, D. M. et al. Two families with familial 

amyotrophic lateral sclerosis are linked to a novel 

locus on chromosome 16q. Am. J. Hum. Genet. 73, 

390–396 (2003).

19.   Hentati, A. et al. Linkage of a commoner form of 

recessive amyotrophic lateral sclerosis to chromosome 

15q15-q22 markers. Neurogenetics 2, 55–60 

(1998).

20.   Sapp, P. et al. Identification of three novel mutations 

in the gene for Cu/Zn superoxide dismutase in 

patients with familial amyotrophic lateral sclerosis. 

Neuromuscul. Disord. 5, 353–357 (1995).

21.   Abalkhail, H., Mitchell, J., Habgood, J., Orrell, R. & 

de Belleroche, J. A new familial amyotrophic lateral 

sclerosis locus on chromosome 16q12.1–16q12.2. 

Am. J. Hum. Genet. 73, 383–389 (2003).

22.   Hong, S. et al. X-linked dominant locus for late-onset 

familial amyotrophic lateral sclerosis. Soc. Neurosci. 

Abstr. 24, 478 (1998).

23.   Hand, C. K. et al. A novel locus for familial 

amyotrophic lateral sclerosis, on chromosome 18q. 

Am. J. Hum. Genet. 70, 251–256 (2002).

24.  Morita, M. et al. A locus on chromosome 9p confers 

susceptibility to ALS and frontotemporal dementia. 

Neurology 66, 839–844 (2006).

25.   Hosler, B. A. et al. Linkage of familial amyotrophic 

lateral sclerosis with frontotemporal dementia to 

chromosome 9q21–q22. JAMA 284, 1664–1669 

(2000).

26.   Andersen, P. M. et al. 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. 4, 62–73 (2003).

27.   Andersen, P. M. et al. Phenotypic heterogeneity in 

motor neuron disease patients with CuZn-superoxide 

dismutase mutations in Scandinavia. Brain 120, 

1723–1737 (1997).

28.   Radunovic, A. et al. Copper and zinc levels in familial 

amyotrophic lateral sclerosis patients with Cu/Zn gene 

mutations. Ann. Neurol. 42, 130–131 (1997).

29.   Yamanaka, K. & Cleveland, D. W. Determinants of 

rapid disease progression in ALS. Neurology 65, 

1859–1860 (2005).

30.   Cudkowicz, M. E., McKenna-Yasek, D., Chen, C., 

Hedley-Whyte, E. T. & Brown, R. H. Jr. Limited 

corticospinal tract involvement in amyotrophic lateral 

sclerosis subjects with the A4V mutation in the 

copper/zinc superoxide dismutase gene [see 

comments]. Ann. Neurol. 43, 703–710 (1998).

31.   Andersen, P. M. 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. Brain 119, 1153–1172

(1996). 

32.   Soares, M. L. 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. Eur. J. Hum. Genet. 12, 225–237 (2004).

33.   Topp, J. D., Gray, N. W., Gerard, R. D. & 

Horazdovsky, B. F. Alsin is a Rab5 and Rac1 guanine 

nucleotide exchange factor. J. Biol. Chem. 23, 

24612–24623 (2004).

34.   Otomo, A. et al. ALS2, a novel guanine nucleotide 

exchange factor for the small GTPase Rab5, is 

implicated in endosomal dynamics. Hum. Mol. Genet. 

12, 1671–1687 (2003).

35.   Kanekura, K. et al. Alsin, the product of ALS2 gene, 

suppresses SOD1 mutant neurotoxicity through 

RhoGEF domain by interacting with SOD1 mutants. 

J. Biol. Chem. 279, 19247–19256 (2004).

36.   Panzeri, C. et al. The first ALS2 missense mutation 

associated with JPLS reveals new aspects of alsin 

biological function. Brain 129, 1710–1719 

(2006).

37.   Yamanaka, K. et al. Unstable mutants in the 

peripheral endosomal membrane component ALS2 

cause early-onset motor neuron disease. Proc. Natl 

Acad. Sci. USA 100, 16041–16046 (2003).

38.   Cai, H. et al. Loss of ALS2 function is insufficient to 

trigger motor neuron degeneration in knock-out mice 

but predisposes neurons to oxidative stress. 

J. Neurosci. 25, 7567–7574 (2005).

39.   Hadano, S. et al. Mice deficient in the Rab5 guanine 

nucleotide exchange factor ALS2/alsin exhibit age-

dependent neurological deficits and altered 

endosome trafficking. Hum. Mol. Genet. 15, 233–250 

(2006).

40.   Chen, Y. Z. 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. Neurobiol. 

Dis. 23, 97–108 (2006).

41.   Skibinski, G. et al. Mutations in the endosomal 

ESCRTIII-complex subunit CHMP2B in 

frontotemporal dementia. Nature Genet. 37, 

806–808 (2005).

42.   Comi, G. P. et al. Cytochrome c oxidase subunit I 

microdeletion in a patient with motor neuron disease. 

Ann. Neurol. 43, 110–116 (1998).

43.   Borthwick, G. M. et al. Motor neuron disease in a 

patient with a mitochondrial tRNAIle mutation. Ann. 

Neurol. 59, 570–574 (2006).

44.   Lambrechts, D. et al. VEGF is a modifier of 

amyotrophic lateral sclerosis in mice and humans and 

protects motoneurons against ischemic death. Nature 

Genet. 34, 383–394 (2003).

45.   Van Vught, P. W. et al. Lack of association between 

VEGF polymorphisms and ALS in a Dutch population. 

Neurology 65, 1643–1645 (2005).

46.   Greenway, M. J. et al. A novel candidate region for 

ALS on chromosome 14q11.2. Neurology 63, 

1936–1938 (2004).

47.   Al-Chalabi, A. et al. Deletions of the heavy 

neurofilament subunit tail in amyotrophic lateral 

sclerosis. Hum. Mol. Genet. 8, 157–164 (1999).

R E V I E W S

720 

|

 SEPTEMBER 2006 

|

 VOLUME 7 

 

www.nature.com/reviews/neuro

©

 

200

6

 

Nature Publishing Group

 

 

48.   Figlewicz, D. A. et al. Variants of the heavy 

neurofilament subunit are associated with the 

development of amyotrophic lateral sclerosis. Hum. 

Mol. Genet. 3, 1757–1761 (1994).

49.   Tomkins, J. et al. Novel insertion in the KSP region of 

the neurofilament heavy gene in amyotrophic lateral 

sclerosis (ALS). Neuroreport 9, 3967–3970 (1998).

50.   Corcia, P. et al. Abnormal SMN1 gene copy number is 

a susceptibility factor for amyotrophic lateral sclerosis. 

Ann. Neurol. 51, 243–246 (2002).

51.   Veldink, J. H. et al. Homozygous deletion of the 

survival motor neuron 2 gene is a prognostic factor in 

sporadic ALS. Neurology 56, 749–752 (2001).

52.   Reaume, A. et al. Motor neurons in Cu/Zn superoxide 

dismutase-deficient mice develop normally but exhibit 

enhanced cell death after axonal injury. Nature Genet. 

13, 43–47 (1996).

53.   Gurney, M. Mutant mice, Cu, Zn superoxide 

dismutase, and motor neuron degeneration. Science 

266, 1586 (1994).

The first description of the transgenic mouse model 

of ALS.

54.   Cleveland, D. W., Laing, N., Hurse, P. V. & 

Brown, R. H. Jr. Toxic mutants in Charcot’s sclerosis 

[letter; comment]. Nature 378, 342–343 (1995).

55.   Beckman, J. S., Carson, M., Smith, C. D. & 

Kuppenol, W. H. ALS, SOD, and peroxynitrite. Nature 

364, 584 (1993).

56.   Wiedau-Pazos, M. et al. Altered reactivity of 

superoxide dismutase in familial amyotrophic lateral 

sclerosis. Science 271, 515–518 (1996).

57.   Estevez, A. G. et al. Induction of nitric oxide-

dependent apoptosis in motor neurons by zinc-

deficient superoxide dismutase. Science 286, 

2498–2500 (1999).

58.   Andrus, P. K., Fleck, T. J., Gurney, M. E. & Hall, E. D. 

Protein oxidative damage in a transgenic mouse 

model of familial amyotrophic lateral sclerosis. 

J. Neurochem. 71, 2041–2048 (1998).

59.   Hall, E., Andrus, P., Oostveen, J., Fleck, T. & Gurney, M. 

Relationship of oxygen radical-induced lipid 

peroxidative damage to disease onset and progression 

in a transgenic model of familial ALS. J. Neurosci. Res. 

53, 66–77 (1998).

60.   Bruijn, L. 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-liked superoxide 

dismutase 1 mutant. Proc. Natl Acad. Sci. USA 94, 

7606–7611 (1997).

61.   Bruijn, L. I. et al. Aggregation and motor neuron toxicity 

of an ALS-linked SOD1 mutant independent from wild-

type SOD1. Science 281, 1851–1854 (1998).

62.   Jaarsma, D. 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. Neurobiol. Dis. 7, 

623–643 (2000).

63.   Deng, H. X. et al. Conversion to the amyotrophic 

lateral sclerosis phenotype is associated with 

intermolecular linked insoluble aggregates of SOD1 in 

mitochondria. Proc. Natl Acad. Sci. USA 103, 

7142–7147 (2006).

64.   Wong, P. C. et al. Copper chaperone for superoxide 

dismutase is essential to activate mammalian Cu/Zn 

superoxide dismutase. Proc. Natl Acad. Sci. USA 97, 

2886–2891 (2000).

65.   Wang, J. et al. Copper-binding-site-null SOD1 causes 

ALS in transgenic mice: aggregates of non-native 

SOD1 delineate a common feature. Hum. Mol. Genet. 

12, 2753–2764 (2003).

66.   Ripps, M. E., Huntley, G. W., Hof, P. R., Morrison, J. H. 

& Gordon, J. W. Transgenic mice expressing an altered 

murine superoxide dismutase gene provide an animal 

model of amyotrophic lateral sclerosis. Proc. Natl 

Acad. Sci. USA 92, 689–693 (1995).

67.   Bush, A. I. Is ALS caused by an altered oxidative 

activity of mutant superoxide dismutase? Nature 

Neurosci. 5, 919; author reply 919–920 (2002).

68.   Jonsson, P. A. et al. Disulphide-reduced superoxide 

dismutase-1 in CNS of transgenic amyotrophic lateral 

sclerosis models. Brain 129, 451–464 (2006).

69.   Johnston, J. A., Dalton, M. J., Gurney, M. E. & 

Kopito, R. R. Formation of high molecular weight 

complexes of mutant Cu,Zn-superoxide dismutase in 

a mouse model for familial amyotrophic lateral 

sclerosis. Proc. Natl Acad. Sci. USA 97, 

12571–12576 (2000).

70.   Wang, J., Xu, G. & Borchelt, D. R. High molecular 

weight complexes of mutant superoxide dismutase 1: 

age-dependent and tissue-specific accumulation. 

Neurobiol. Dis. 9, 139–148 (2002).

71.   Ray, S. S. et al. An intersubunit disulfide bond prevents 

in vitro aggregation of a superoxide dismutase-1 

mutant linked to familial amytrophic lateral sclerosis. 

Biochemistry 43, 4899–4905 (2004).

72.   Matsumoto, G., Kim, S. & Morimoto, R. I. Huntingtin 

and mutant SOD1 form aggregate structures with 

distinct molecular properties in human cells. J. Biol. 

Chem. 281, 4477–4485 (2006).

73.   Sato, T. et al. Rapid disease progression correlates 

with instability of mutant SOD1 in familial ALS. 

Neurology 65, 1954–1957 (2005).

74.   Lindberg, M. J., Bystrom, R., Boknas, N., 

Andersen, P. M. & Oliveberg, M. Systematically 

perturbed folding patterns of amyotrophic lateral 

sclerosis (ALS)-associated SOD1 mutants. Proc. Natl 

Acad. Sci. USA 102, 9754–9759 (2005).

75.   Shinder, G. A., Lacourse, M.-C., Minotti, S. & Durham, 

H. D. Mutant cu/zn superoxide dismutase proteins 

have altered solubility and interact with heat shock/

stress proteins in models of amyotrophic lateral 

sclerosis. J. Biol. Chem. 276, 12791–12796 (2001).

76.   Pasinelli, P. et al. Amyotrophic lateral sclerosis-

associated SOD1 mutant proteins bind and aggregate 

with Bcl-2 in spinal cord mitochondria. Neuron 43, 

19–30 (2004).

77.   Guegan, C. & Przedborski, S. Programmed cell death 

in amyotrophic lateral sclerosis. J. Clin. Invest. 111, 

153–161 (2003).

78.   Durham, H., Roy, J., Dong, L. & Figlewicz, D. 

Aggregation of mutant Cu/Zn superoxide dismutase 

proteins in a culture model of ALS. J. Neuropath. Exp. 

Neurol. 56, 523–530 (1997).

79.   Pasinelli, P., Borchelt, D. R., Houseweart, M. K., 

Cleveland, D. W. & Brown, R. H. Jr. Caspase-1 is 

activated in neural cells and tissue with amyotrophic 

lateral sclerosis-associated mutations in copper-zinc 

superoxide dismutase. Proc. Natl Acad. Sci. USA 95, 

15763–15768 (1998).

80.   Pasinelli, P., Houseweart, M. K., Brown, R. H. Jr & 

Cleveland, D. W. Caspase-1 and -3 are sequentially 

activated in motor neuron death in Cu,Zn superoxide 

dismutase-mediated familial amyotrophic lateral 

sclerosis. Proc. Natl Acad. Sci. USA 97, 

13901–13906 (2000).

81.   Vukosavic, S. et al. Delaying caspase activation by Bcl-

2: a clue to disease retardation in a transgenic mouse 

model of amyotrophic lateral sclerosis. J. Neurosci. 

20, 9119–9125 (2000).

82.   Li, M. et al. Functional role of caspase-1 and caspase-3 

in an ALS transgenic mouse model. Science 288, 

335–339 (2000).

83.   Vukosavic, S., Dubois-Dauphin, M., Romero, N. & 

Przedborski, S. Bax and Bcl-2 intercation in a 

transgenic mouse model of familial amyotrophic 

lateral sclerosis. J. Neurochem. 73, 2460–2468 

(1999).

84.   Bacman, S. R., Bradley, W. G. & Moraes, C. T. 

Mitochondrial involvement in amyotrophic lateral 

sclerosis: trigger or target? Mol. Neurobiol. 33, 

113–131 (2006).

85.   Boston-Howes, W. et al. Caspase-3 cleaves and 

inactivates the glutamate transporter EAAT2. J. Biol. 

Chem. 281, 14076–14084 (2006).

86.   Guegan, C., Vila, M., Rosoklija, G., Hays, A. P. & 

Przedborski, S. Recruitment of the mitochondrial-

dependent apoptotic pathway in amyotrophic lateral 

sclerosis. J. Neurosci. 21, 6569–6576 (2001).

87.   Rabizadeh, S. 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. 

Proc. Natl Acad. Sci. USA 92, 3024–3028 (1995).

88.   Alexianu, M. E., Kozovska, M. & Appel, S. H. Immune 

reactivity in a mouse model of familial ALS correlates 

with disease progression. Neurology 57, 1282–1289 

(2001).

89.   Elliott, J. L. Cytokine upregulation in a murine model 

of familial amyotrophic lateral sclerosis. Brain Res. 

Mol. Brain Res. 95, 172–178 (2001).

90.   Almer, G. et al. Increased expression of the pro-

inflammatory enzyme cyclooxygenase-2 in 

amyotrophic lateral sclerosis. Ann. Neurol. 49, 

176–185 (2001).

91.   Hensley, K. et al. Primary glia expressing the G93A-

SOD1 mutation present a neuroinflammatory 

phenotype and provide a cellular system for studies of 

glial inflammation. J. Neuroinflammation 3, 2 (2006).

92.   Raoul, C. et al. Motoneuron death triggered by a 

specific pathway downstream of Fas. potentiation by 

ALS-linked SOD1 mutations. Neuron 35, 1067–1083 

(2002).

93.   Raoul, C. et al. Chronic activation in presymptomatic 

amyotrophic lateral sclerosis (ALS) mice of a feedback 

loop involving Fas, Daxx, and FasL. Proc. Natl Acad. 

Sci. USA 103, 6007–6012 (2006).

94.   Kikuchi, H. et al. Spinal cord endoplasmic reticulum 

stress associated with a microsomal accumulation of 

mutant superoxide dismutase-1 in an ALS model. 

Proc. Natl Acad. Sci. USA 103, 6025–6030 (2006).

95.   Urushitani, M. et al. Chromogranin-mediated 

secretion of mutant superoxide dismutase proteins 

linked to amyotrophic lateral sclerosis. Nature 

Neurosci. 9, 108–118 (2006).

96.   Atsumi, T. The ultrastructure of intramuscular nerves 

in amyotrophic lateral sclerosis. Acta Neuropath. 55, 

193–198 (1981).

97.   Afifi, A., Aleu, F., Goodgold, J. & MacKay, B. 

Ultrastructure of atrophic muscle in amyotrophic 

lateral sclerosis. Neurology 16, 475–481 (1966).

98.   Wiedemann, F. R. et al. Impairment of mitochondrial 

function in skeletal muscle of patients with 

amyotrophic lateral sclerosis. J. Neurol. Sci. 156, 

65–72 (1998).

99.   Siklos, L. et al. Ultrastructural evidence for altered 

calcium in motor nerve terminals in amyotrophic 

lateral sclerosis. Ann. Neurol. 39, 203–216 (1996).

100.  Higgins, C. M., Jung, C. & Xu, Z. ALS-associated 

mutant SOD1G93A causes mitochondrial vacuolation 

by expansion of the intermembrane space and by 

involvement of SOD1 aggregation and peroxisomes. 

BMC Neurosci. 4, 16 (2003).

101.  Kong, J. & Xu, Z. Massive mitochondrial degeneration 

in motor neurons triggers the onset of amyotrophic 

lateral sclerosis in mice expressing a mutant SOD1. 

J. Neurosci. 18, 3241–3250 (1998).

102.  Bendotti, C. 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. J. Neurol. 

Sci. 191, 25–33 (2001).

103.  Sasaki, S., Warita, H., Murakami, T., Abe, K. & Iwata, M. 

Ultrastructural study of mitochondria in the spinal cord 

of transgenic mice with a G93A mutant SOD1 gene. 

Acta Neuropathol. (Berl.) 107, 461–474 (2004).

104.  Rizzardini, M. et al. Neurodegeneration induced by 

complex I inhibition in a cellular model of familial 

amyotrophic lateral sclerosis. Brain Res. Bull. 69, 

465–474 (2006).

105.  Jung, C., Higgins, C. M. & Xu, Z. Mitochondrial 

electron transport chain complex dysfunction in a 

transgenic mouse model for amyotrophic lateral 

sclerosis. J. Neurochem. 83, 535–545 (2002).

106.  Damiano, M. et al. Neural mitochondrial Ca

2+

 

capacity impairment precedes the onset of motor 

symptoms in G93A Cu/Zn-superoxide dismutase 

mutant mice. J. Neurochem. 96, 1349–1361 (2006).

107.  Menzies, F. M. et al. Mitochondrial dysfunction in a 

cell culture model of familial amyotrophic lateral 

sclerosis. Brain 125, 1522–1533 (2002).

108.  Klivenyi, P. et al. Neuroprotective effects of creatine in 

a transgenic animal model of amyotrophic lateral 

sclerosis. Nature Med. 5, 347–350 (1999).

109.  Zhu, S. et al. Minocycline inhibits cytochrome c 

release and delays progression of amyotrophic lateral 

sclerosis in mice. Nature 417, 74–78 (2002).

110.  Higgins, C. M., Jung, C., Ding, H. & Xu, Z. Mutant Cu, 

Zn superoxide dismutase that causes motoneuron 

degeneration is present in mitochondria in the CNS. 

J. Neurosci. 22, RC215 (2002).

111.  Mattiazzi, M. et al. Mutated human SOD1 causes 

dysfunction of oxidative phosphorylation in 

mitochondria of transgenic mice. J. Biol. Chem. 277, 

29626–29633 (2002).

112.  Liu, J. et al. Toxicity of familial ALS-linked SOD1 

mutants from selective recruitment to spinal 

mitochondria. Neuron 43, 5–17 (2004).

113.  Okado-Matsumoto, A. & Fridovich, I. Amyotrophic 

lateral sclerosis: a proposed mechanism. Proc. Natl 

Acad. Sci. USA 99, 9010–9014 (2002).

114.  Takeuchi, H. K., Ishigaki, Y., Doyu, S. M. & Sobue, G. 

Mitochondrial localization of mutant superoxide 

dismutase 1 triggers caspase-dependent cell death in 

a cellular model of familial amyotrophic lateral 

sclerosis. J. Biol. Chem. 277, 50966–50972 (2002).

115.  Bergemalm, D. et al. Overloading of stable and 

exclusion of unstable human superoxide dismutase-1 

variants in mitochondria of murine amyotrophic lateral 

sclerosis models. J. Neurosci. 26, 4147–4154 (2006).

R E V I E W S

NATURE REVIEWS 

|