PDF herunterladen
Semin Neurol 2001; 21(2): 131-140
DOI: 10.1055/s-2001-15260
Copyright © 2001 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA. Tel.: +1(212) 584-4662

Amyotrophic Lateral Sclerosis: Pathogenesis

Robert H. Brown, Jr1 , Wim Robberecht2
  • 1Day Neuromuscular Research Laboratory, Harvard Medical School, Department of Neurology, Massachusetts General Hospital, Boston, Massachusetts and
  • 2Department of Neurology, University of Leuven School of Medicine, University Hospital Gasthuisberg, Leuven, Belgium
Weitere Informationen

Publikationsverlauf

Publikationsdatum:
31. Dezember 2001 (online)

    Lizenzen und Reprints

ABSTRACT

Amyotrophic lateral sclerosis (ALS) is a devastating paralytic disorder caused by motor neuron degeneration. A subgroup of familial cases arises from mutations in the gene encoding cytosolic superoxide dismutase (SOD1). This review considers insight now being gained into ALS pathogenesis from the study of mutant SOD1 protein and its possible mechanisms of adverse effect on nerve cells. Also discussed are the status of other genetic forms of ALS and the elusive question of why this disorder so specifically targets motor neurons. Ultimately, it is hoped that insights from these types of studies will improve the prospects for developing meaningful therapies of ALS.

KEYWORD

Amyotrophic lateral sclerosis

REFERENCES

  • 1 Mulder D W, Kurland L T, Offord K P, Beard C M. Familial adult motor neuron disease: amyotrophic lateral sclerosis.  Neurology . 1986;  36 511-517
    PubMedGoogle Scholar
  • 2 Rosen D R, Siddique T, Patterson D. Mutations in Cu/Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis.  Nature . 1993;  362 59-62
    CrossrefPubMedGoogle Scholar
  • 3 Robberecht W, Aguirre T, Van den Bosch L, Tilkin P, Cassiman J J, Mathijs G. D 90 A heterozygosity in the SOD1 gene is associated with familial and apparently sporadic amyotrophic lateral sclerosis.  Neurology . 1996;  47 1336-1339
    PubMedGoogle Scholar
  • 4 Andersen P M, Nilsson P, Ala-Hurula V. Amyotrophic lateral sclerosis associated with homozygosity for an Asp90Ala mutation in CuZn-superoxide dismutase.  Nat Genet . 1995;  10 61-66
    CrossrefPubMedGoogle Scholar
  • 5 Al-Chalabi A, Andersen P M, Chioza B. 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 2045-2050
    CrossrefPubMedGoogle Scholar
  • 6 Juneja T, Pericak-Vance M A, Laing N G, Dave S, Siddique T. Prognosis in familial amyotrophic lateral sclerosis: progression and survival in patients with glu100gly and ala4val mutations in Cu,Zn superoxide dismutase.  Neurology . 1997;  48 55-57
    PubMedGoogle Scholar
  • 7 Cudkowicz M E, McKenna-Yasek D, Sapp P E. Epidemiology of mutations in superoxide dismutase in amyotrophic lateral sclerosis.  Ann Neurol . 1997;  41 210-221
    CrossrefPubMedGoogle Scholar
  • 8 Fridovich I. Superoxide radical and superoxide dismutases.  Annu Rev Biochem . 1995;  64 97-112
    CrossrefPubMedGoogle Scholar
  • 9 Bowling A C, Schulz J B, Brown Jr H R, Beal M F. Superoxide dismutase activity, oxidative damage and mitochondrial energy metabolism in familial and sporadic amyotrophic lateral sclerosis.  J Neurochem . 1993;  61 2322-2325
    PubMedGoogle Scholar
  • 10 Robberecht W, Sapp P, Viaene M K. Cu/Zn superoxide dismutase activity in familial and sporadic amyotrophic lateral sclerosis.  J Neurochem . 1994;  62 384-387
    PubMedGoogle Scholar
  • 11 Bowling A C, Barkowski E E, McKenna-Yasek D. Superoxide dismutase concentration and activity in familial amyotrophic lateral sclerosis.  J Neurochem . 1995;  64 2366-2369
    PubMedGoogle Scholar
  • 12 Deng H X, Hentati A, Tainer J A. Amyotrophic lateral sclerosis and structural defects in Cu,Zn superoxide dismutase.  Science . 1993;  261 1047-1051
    PubMedGoogle Scholar
  • 13 Puymirat J, Cossette L, Gosselin F, Bouchard J P. Red blood cell Cu/Zn superoxide dismutase activity in sporadic amyotrophic lateral sclerosis.  J Neurol Sci . 1994;  127 121-123
    CrossrefPubMedGoogle Scholar
  • 14 Borchelt D R, Lee M K, Slunt H S. Superoxide dismutase 1 with mutations linked to familial amyotrophic lateral sclerosis possesses significant activity.  Proc Natl Acad Sci U S A . 1994;  91 8292-8296
    PubMedGoogle Scholar
  • 15 Beal M F, Ferrante R J, Browne S E, Matthews R T, Kowall N W, Brown Jr H R. Increased 3-nitrotyrosine in both sporadic and familial amyotrophic lateral sclerosis.  Ann Neurol . 1997;  42 644-654
    CrossrefPubMedGoogle Scholar
  • 16 Hall E D, Andrus P K, Oostveen J A, Fleck T J, Gurney M E. Relationship of oxygen radical-induced lipid peroxidative damage to disease onset and progression in a transgenic model of familial ALS.  J Neurosci Res . 1998;  53 66-77
    CrossrefPubMedGoogle Scholar
  • 17 Smith R G, Henry Y K, Mattson M P, Appel S H. Presence of 4-hydroxynonenal in cerebrospinal fluid of patients with sporadic amyotrophic lateral sclerosis.  Ann Neurol . 1998;  44 696-699
    CrossrefPubMedGoogle Scholar
  • 18 Reaume A G, Elliott J L, Hoffman E K. Motor neurons in Cu/Zn superoxide dismutase-deficient mice develop normally but exhibit enhanced cell death after axonal injury.  Nat Genet . 1996;  13 43-47
    CrossrefPubMedGoogle Scholar
  • 19 Gurney M E, Pu H, Chiu A Y. Motor neuron degeneration in mice that express a human Cu,Zn superoxide dismutase mutation.  Science . 1994;  264 1772-1775
    CrossrefPubMedGoogle Scholar
  • 20 Nishida C R, Gralla E B, Valentine J S. Characterization of three yeast copper-zinc superoxide dismutase mutants analogous to those coded for in familial amyotrophic lateral sclerosis.  Proc Natl Acad Sci U S A . 1994;  91 9906-9910
    PubMedGoogle Scholar
  • 21 Carri M T, Battistoni A, Polizio F, Desideri A, Rotilio G. Impaired copper binding by the H46R mutant of human Cu,Zn superoxide dismutase, involved in amyotrophic lateral sclerosis.  FEBS Lett . 1994;  356 314-316
    CrossrefPubMedGoogle Scholar
  • 22 Crow J P, Sampson J B, Zhuang Y, Thompson J A, Beckman J S. Decreased zinc affinity of amyotrophic lateral sclerosis- associated superoxide dismutase mutants leads to enhanced catalysis of tyrosine nitration by peroxynitrite.  J Neurochem . 1997;  69 1936-1944
    PubMedGoogle Scholar
  • 23 Estevez A G, Crow J P, Sampson J B. Induction of nitric oxide-dependent apoptosis in motor neurons by zinc-deficient superoxide dismutase.  Science . 1999;  286 2498-2500
    CrossrefPubMedGoogle Scholar
  • 24 Beckman J S, Carson M, Smith C D, Koppenol W H. ALS, SOD, and peroxynitrite.  Nature . 1993;  364 584
    CrossrefPubMedGoogle Scholar
  • 25 Crow J P, Ye Y Z, Strong M, Kirk M, Barnes S, Beckman J S. Superoxide dismutase catalyzes nitration of tyrosines by peroxynitrite in the rod and head domains of neurofilament-L.  J Neurochem . 1997;  69 1945-1953
    PubMedGoogle Scholar
  • 26 Bruijn L I, Beal M F, Becher M W. 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.  Proc Natl Acad Sci U S A . 1997;  94 7606-7611
    CrossrefPubMedGoogle Scholar
  • 27 Beal M F, Ferrante R J, Browne S E, Matthews R T, Kowall N W, Brown Jr H R. Increased 3-nitrotyrosine and oxidative damage in mice with a human copper/zinc superoxide dismutase mutation.  Ann Neurol . 1997;  42 326-334
    CrossrefPubMedGoogle Scholar
  • 28 Wiedau-Pazos M, Goto J J, Rabizadeh S. Altered reactivity of superoxide dismutase in familial amyotrophic lateral sclerosis.  Science . 1996;  271 515-518
    PubMedGoogle Scholar
  • 29 Yim M B, Kang J H, Yim H S, Kwak H S, Chock P B, Stadtman E R. A gain-of-function mutation of an amyotrophic lateral sclerosis-associated Cu,Zn-superoxide dismutase mutant: an enhancement of free radical formation due to a decrease in Km for hydrogen peroxide.  Proc Natl Acad Sci U S A . 1996;  93 5709-5714
    CrossrefPubMedGoogle Scholar
  • 30 Yim H S, Kang J H, Chock P B, Stadtman E R, Yim M B. A familial amyotrophic lateral sclerosis-associated A4V Cu,Zn superoxide dismutase mutant has a lower Km for hydrogen peroxide. Correlation between severity and the Km value.  J Biol Chem . 1997;  272 8861-8863
    CrossrefPubMedGoogle Scholar
  • 31 Bogdanov M B, Ramos L E, Xu Z, Beal M F. Elevated ``hydroxyl radical'' generation in vivo in an animal model of amyotrophic lateral sclerosis.  J Neurochem . 1998;  71 1321-1324
    PubMedGoogle Scholar
  • 32 Bruijn L I, Houseweart M K, Kato S. Aggregation and motor neuron toxicity of an ALS-linked SOD1 mutant independent from wild-type SOD1.  Science . 1998;  281 1851-1854
    CrossrefPubMedGoogle Scholar
  • 33 Zona C, Ferri A, Gabbianelli R. Voltage-activated sodium currents in a cell line expressing a Cu,Zn superoxide dismutase typical of familial ALS.  Neuroreport . 1998;  9 3515-3518
    PubMedGoogle Scholar
  • 34 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 . 1998;  18 3241-3250
    PubMedGoogle Scholar
  • 35 Wong P C, Pardo C A, Borchelt D R. An adverse property of a familial ALS-linked SOD1 mutation causes motor neuron disease characterized by vacuolar degeneration of mitochondria.  Neuron . 1995;  14 1105-1116
    CrossrefPubMedGoogle Scholar
  • 36 Williamson T L, Cleveland D W. Slowing of axonal transport is a very early event in the toxicity of ALS-linked SOD1 mutants to motor neurons.  Nat Neurosci . 1999;  2 50-56
    CrossrefPubMedGoogle Scholar
  • 37 Borchelt D R, Wong P C, Becher M W. Axonal transport of mutant superoxide dismutase 1 and focal axonal abnormalities in the proximal axons of transgenic mice.  Neurobiol Dis . 1998;  5 27-35
    CrossrefPubMedGoogle Scholar
  • 38 Rothstein J D, Bristol L A, Hosler B, Brown Jr H R, Kuncl R W. Chronic inhibition of superoxide dismutase produces apoptotic death of spinal neurons.  Proc Natl Acad Sci U S A . 1994;  91 4155-4159
    PubMedGoogle Scholar
  • 39 Durham H D, Roy J, Dong L, Figlewicz D A. Aggregation of mutant Cu/Zn superoxide dismutase proteins in a culture model of ALS.  J Neuropathol Exp Neurol . 1997;  56 523-530
    PubMedGoogle Scholar
  • 40 Rabizadeh S, Gralla E B, Borchelt D R. 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 U S A . 1995;  92 3024-3028
    PubMedGoogle Scholar
  • 41 Ghadge G D, Lee J P, Bindokas V P. Mutant superoxide dismutase-1-linked familial amyotrophic lateral sclerosis: molecular mechanisms of neuronal death and protection.  J Neurosci . 1997;  17 8756-8766
    PubMedGoogle Scholar
  • 42 Pasinelli P, Borchelt D R, Houseweart M K, Cleveland D W, Brown Jr H R. Caspase-1 is activated in neural cells and tissue with amyotrophic lateral sclerosis-associated mutations in copper-zinc superoxide dismutase.  Proc Natl Acad Sci U S A . 1998;  95 15763-15768
    CrossrefPubMedGoogle Scholar
  • 43 Li M, Ona V O, Guegan C. Functional role of caspase-1 and caspase-3 in an ALS transgenic mouse model.  Science . 2000;  288 335-339
    CrossrefPubMedGoogle Scholar
  • 44 Friedlander R M, Brown R H, Gagliardini V, Wang J, Yuan J. Inhibition of ICE slows ALS in mice.  Nature . 1997;  388 31
    PubMedGoogle Scholar
  • 45 Kostic V, Jackson-Lewis V, de Bilbao F, Dubois-Dauphin M, Przedborski S. Bcl-2: prolonging life in a transgenic mouse model of familial amyotrophic lateral sclerosis.  Science . 1997;  277 559-562
    CrossrefPubMedGoogle Scholar
  • 46 Li M, Ona V O, Guegan C. Functional role of caspase-1 and caspase-3 in an ALS transgenic mouse model.  Science . 2000;  288 335-339
    CrossrefPubMedGoogle Scholar
  • 47 Figlewicz D A, Krizus A, Martinoli M G. Variants of the heavy neurofilament subunit are associated with the development of amyotrophic lateral sclerosis.  Hum Mol Genet . 1994;  3 1757-1761
    PubMedGoogle Scholar
  • 48 Vechio J D, Bruijn L I, Xu Z. Sequence variants in human neurofilament proteins: absence of linkage to familial amyotrophic lateral sclerosis.  Ann Neurol . 1996;  40 603-610
    CrossrefPubMedGoogle Scholar
  • 49 Chance P F, Rabin B A, Ryan S G. Linkage of the gene for an autosomal dominant form of juvenile amyotrophic lateral sclerosis to chromosome 9q34.  Am J Hum Genet . 1998;  62 633-640
    CrossrefPubMedGoogle Scholar
  • 50 Hosler B A, Siddique T, Sapp P C. Linkage of familial amyotrophic lateral sclerosis with frontotemporal dementia to chromosome 9q21-q22.  JAMA . 2000;  284 1664-1669
    CrossrefPubMedGoogle Scholar
  • 51 Hentati A, Ouahchi K, Pericak-Vance M A. Linkage of a commoner form of recessive amyotrophic lateral sclerosis to chromosome 15q15-q22 markers.  Neurogenetics . 1998;  2 55-60
    CrossrefPubMedGoogle Scholar
  • 52 Hentati A, Bejaoui K, Pericak-Vance M A. Linkage of recessive familial amyotrophic lateral sclerosis to chromosome 2q33-q35.  Nat Genet . 1994;  3 425-428
    PubMedGoogle Scholar
  • 53 Hosler B A, Sapp P C, Berger R. Refined mapping and characterization of the recessive familial amyotrophic lateral sclerosis locus (ALS2) on chromosome 2q33.  Neurogenetics . 1998;  2 34-42
    CrossrefPubMedGoogle Scholar
  • 54 Kennedy W B, Alter M, Sung J G. Report of an X-linked form of spinal muscular atrophy.  Neurology . 1968;  18 671-680
    CrossrefPubMedGoogle Scholar
  • 55 La Spada R A, Wilson E M, Lubahn D B, Harding A E, Fischbeck K H. Androgen receptor gene mutations in X-linked spinal and bulbar muscular atrophy.  Nature . 1991;  352 77-79
    CrossrefPubMedGoogle Scholar
  • 56 La Spada R A, Roling D B, Harding A E. Meiotic stability and genotype-phenotype correlation of the trinucleotide repeat in X-linked spinal and bulbar muscular atrophy.  Nat Genet . 1992;  2 301-304
    PubMedGoogle Scholar
  • 57 Doyu M, Sobue G, Mukai E. Severity of X-linked recessive bulbospinal neuronopathy correlates with size of the tandem CAG repeat in androgen receptor gene.  Ann Neurol . 1992;  32 707-710
    CrossrefPubMedGoogle Scholar
  • 58 Sanchez I, Xu C J, Juo P. Caspase-8 is required for cell death induced by expanded polyglutamine repeats.  Neuron . 1999;  22 623-633
    CrossrefPubMedGoogle Scholar
  • 59 Aoki M, Lin C L, Rothstein J D. Mutations in the glutamate transporter EAAT2 gene do not cause abnormal EAAT2 transcripts in amyotrophic lateral sclerosis.  Ann Neurol . 1998;  43 645-653
    CrossrefPubMedGoogle Scholar
  • 60 Trotti D, Aoki M, Pasinelli P. Amyotrophic lateral sclerosis-linked glutamate transporter mutant has impaired glutamate clearance capacity.  J Biol Chem . 2001;  276 576-582
    PubMedGoogle Scholar
  • 61 Comi G P, Bordoni A, Salani S. Cytochrome c oxidase subunit I microdeletion in a patient with motor neuron disease.  Ann Neurol . 1998;  43 110-116
    CrossrefPubMedGoogle Scholar
  • 62 Olkowski Z. Mutant AP endonuclease in patients with amyotrophic lateral sclerosis.  Neuroreport . 1998;  9 239-242
    PubMedGoogle Scholar
  • 63 Hayward C, Colville S, Swingler R J, Brock D J. Molecular genetic analysis of the APEX nuclease gene in amyotrophic lateral sclerosis.  Neurology . 1999;  52 1899-1901
    PubMedGoogle Scholar
  • 64 Al-Chalabi A, Enayat Z E, Bakker M C. Association of apolipoprotein E epsilon 4 allele with bulbar-onset motor neuron disease.  Lancet . 1996;  347 159-160
    CrossrefPubMedGoogle Scholar
  • 65 Moulard B, Sefiani A, Laamri A. Apolipoprotein E genotyping in sporadic amyotrophic lateral sclerosis: evidence for a major influence on the clinical presentation and prognosis.  J Neurol Sci . 1996;  139 34-37
    CrossrefPubMedGoogle Scholar
  • 66 Moulard B, Salachas F, Chassande B. Association between centromeric deletions of the SMN gene and sporadic adult-onset lower motor neuron disease.  Ann Neurol . 1998;  43 640-644
    CrossrefPubMedGoogle Scholar
  • 67 Giess R, Beck M, Goetz R, Nitsch R M, Toyka K V, Sendtner M. Potential role of LIF as a modifier gene in the pathogenesis of amyotrophic lateral sclerosis.  Neurology . 2000;  54 1003-1005
    PubMedGoogle Scholar
  • 68 Tomblyn M, Kasarskis E J, Xu Y, St. Clair K D. Distribution of MnSOD polymorphisms in sporadic ALS patients.  J Mol Neurosci . 1998;  10 65-66
    PubMedGoogle Scholar
  • 69 Shaw P J, Ince P G. Glutamate, excitotoxicity and amyotrophic lateral sclerosis.  J Neurol . 1997;  244 S3-S14
    PubMedGoogle Scholar
  • 70 Doble A. The role of excitotoxicity in neurodegenerative disease: implications for therapy.  Pharmacol Ther . 1999;  8 163-221
    PubMedGoogle Scholar
  • 71 Lacomblez L, Bensimon G, Leigh P N, Guillet P, Meininger V. Dose-ranging study of riluzole in amyotrophic lateral sclerosis. Amyotrophic Lateral Sclerosis/Riluzole Study Group II.  Lancet . 1996;  347 1425-1431
    CrossrefPubMedGoogle Scholar
  • 72 Bensimon G, Lacomblez L, Meininger V. A controlled trial of riluzole in amyotrophic lateral sclerosis. ALS/Riluzole Study Group.  N Engl J Med . 1994;  330 585-591
    CrossrefPubMedGoogle Scholar
  • 73 Gurney M E, Cutting F B, Zhai P. Benefit of vitamin E, riluzole, and gabapentin in a transgenic model of familial amyotrophic lateral sclerosis.  Ann Neurol . 1996;  39 147-157
    CrossrefPubMedGoogle Scholar
  • 74 Rothstein J D, Martin L J, Kuncl R W. Decreased glutamate transport by the brain and spinal cord in amyotrophic lateral sclerosis.  N Engl J Med . 1992;  326 1464-1468
    CrossrefPubMedGoogle Scholar
  • 75 Rothstein J D, Van Kammen M, Levez A I, Martin L J, Kuncl R W. Selective loss of glial glutamate transporter GLT-1 in amyotrophic lateral sclerosis.  Ann Neurol . 1995;  38 73-84
    CrossrefPubMedGoogle Scholar
  • 76 Lin C L. Aberrant RNA processing in a neurodegenerative disease: the cause for absent EAAT2, a glutamate transporter, in amyotrophic lateral sclerosis.  Neuron . 1998;  20 589-602
    CrossrefPubMedGoogle Scholar
  • 77 Trotti D, Rolfs A, Danbolt N C, Brown Jr H R, Hediger M A. SOD1 mutants linked to amyotrophic lateral sclerosis selectively inactivate a glial glutamate transporter.  Nat Neurosci . 1999;  2 427-433
    CrossrefPubMedGoogle Scholar
  • 78 Alexander G M, Deitch J S, Seeburger J L, Del Valle L, Heiman-Patterson T D. Elevated cortical extracellular fluid glutamate in transgenic mice expressing human mutant (G93A) Cu/Zn superoxide dismutase.  J Neurochem . 2000;  74 1666-1673
    CrossrefPubMedGoogle Scholar
  • 79 Rothstein J D, Jin L, Dykes-Hoberg M, Kuncl R W. Chronic inhibition of glutamate uptake produces a model of slow neurotoxicity.  Proc Natl Acad Sci U S A . 1993;  90 6591-6595
    PubMedGoogle Scholar
  • 80 Beal M F. Does impairment of energy metabolism result in excitotoxic neuronal death in neurodegenerative illnesses?.  Ann Neurol . 1992;  31 119-130
    CrossrefPubMedGoogle Scholar
  • 81 Carriedo S G, Sensi S L, Yin H Z, Weiss J H. AMPA exposures induce mitochondrial Ca2+ overload and ROS generation in spinal motor neurons in vitro.  J Neurosci . 2000;  20 240-250
    PubMedGoogle Scholar
  • 82 Carri M T, Ferri A, Battistoni A. Expression of a Cu,Zn superoxide dismutase typical of familial amyotrophic lateral sclerosis induces mitochondrial alteration and increase of cytosolic Ca2+ concentration in transfected neuroblastoma SH-SY5Y cells.  FEBS Lett . 1997;  414 365-368
    CrossrefPubMedGoogle Scholar
  • 83 Siklos L, Engelhardt J, Harati Y, Smith R G, Joo F, Appel S H. Ultrastructural evidence for altered calcium in motor nerve terminals in amyotrophic lateral sclerosis.  Ann Neurol . 1996;  39 203-216
    CrossrefPubMedGoogle Scholar
  • 84 Siklos L, Engelhardt J I, Alexianu, M E, Gurney M E, Siddique T, Appel S H. Intracellular calcium parallels motoneuron degeneration in SOD-1 mutant mice.  J Neuropathol Exp Neurol . 1998;  57 571-587
    PubMedGoogle Scholar
  • 85 Mosier D R, Baldelli P, Delbono O. Amyotrophic lateral sclerosis immunoglobulins increase Ca2+ currents in a motoneuron cell line.  Ann Neurol . 1995;  37 102-109
    PubMedGoogle Scholar
  • 86 Alexianu M E, Mohamed A H, Smith R G, Colom L V, Appel S H. Apoptotic cell death of a hybrid motoneuron cell line induced by immunoglobulins from patients with amyotrophic lateral sclerosis.  J Neurochem . 1994;  63 2365-2368
    PubMedGoogle Scholar
  • 87 Smith R G, Alexianu M E, Crawford G, Nyormoi O, Stefani E, Appel S H. Cytotoxicity of immunoglobulins from amyotrophic lateral sclerosis patients on a hybrid motoneuron cell line.  Proc Natl Acad Sci U S A . 1994;  91 3393-3397
    PubMedGoogle Scholar
  • 88 Smith R G, Hamilton S, Hofmann F. Serum antibodies to L-type calcium channels in patients with amyotrophic lateral sclerosis.  N Engl J Med . 1992;  327 1721-1728
    PubMedGoogle Scholar
  • 89 Hugon J, Vallat J M, Spencer P S, Leboutet M J, Barthe D. Kainic acid induces early and delayed degenerative neuronal changes in rat spinal cord.  Neurosci Lett . 1989;  104 258-262
    CrossrefPubMedGoogle Scholar
  • 90 Ikonomidou C, Qin Qin Y, Labruyere J, Olney J W. Motor neuron degeneration induced by excitotoxin agonists has features in common with those seen in the SOD-1 transgenic mouse model of amyotrophic lateral sclerosis.  J Neuropathol Exp Neurol . 1996;  55 211-224
    PubMedGoogle Scholar
  • 91 Van Den Bosch L, Vandenberghe W, Klaassen H, Van Houtte E, Robberecht W. Ca2+-permeable AMPA receptors and selective vulnerability of motor neurons.  J Neurol Sci . 2000;  180 29-34
    CrossrefPubMedGoogle Scholar
  • 92 Vandenberghe W, Ihle E C, Patneau D K, Robberecht W, Brorson J R. AMPA receptor current density, not desensitization, predicts selective motoneuron vulnerability.  J Neurosci . 2000;  20 7158-7166
    PubMedGoogle Scholar
  • 93 Vandenberghe W, Robberecht W, Brorson J R. AMPA receptor calcium permeability, GluR2 expression, and selective motoneuron vulnerability.  J Neurosci . 2000;  20 123-132
    PubMedGoogle Scholar
  • 94 Takuma H, Kwak S, Yoshizawa T, Kanazawa I. Reduction of GluR2 RNA editing, a molecular change that increases calcium influx through AMPA receptors, selective in the spinal ventral gray of patients with amyotrophic lateral sclerosis.  Ann Neurol . 1999;  46 806-815
    CrossrefPubMedGoogle Scholar
  • 95 Palecek J, Lips M B, Keller B U. Calcium dynamics and buffering in motoneurones of the mouse spinal cord.  J Physiol (Lond) . 1999;  520 485-502
    CrossrefPubMedGoogle Scholar
  • 96 Vanselow B K, Keller B U. Calcium dynamics and buffering in oculomotor neurones from mouse that are particularly resistant during amyotrophic lateral sclerosis (ALS)-related motoneurone disease.  J Physiol (Lond) . 2000;  525 433-445
    CrossrefPubMedGoogle Scholar
  • 97 Alexianu M E, Ho B K, Mohamed A H, La Bella V, Smith R G, Appel S H. The role of calcium-binding proteins in selective motoneuron vulnerability in amyotrophic lateral sclerosis.  Ann Neurol . 1994;  36 846-858
    CrossrefPubMedGoogle Scholar
  • 98 Elliott J L, Snider W D. Parvalbumin is a marker of ALS-resistant motor neurons.  Neuroreport . 1995;  6 449-452
    PubMedGoogle Scholar
  • 99 Ince P, Stout N, Shaw P. Parvalbumin and calbindin D-28k in the human motor system and in motor neuron disease.  Neuropathol Appl Neurobiol . 1993;  19 291-299
    PubMedGoogle Scholar
  • 100 Reiner A, Medina L, Figueredo-Cardenas G, Anfinson S. Brainstem motoneuron pools that are selectively resistant in amyotrophic lateral sclerosis are preferentially enriched in parvalbumin: evidence from monkey brainstem for a calcium-mediated mechanism in sporadic ALS.  Exp Neurol . 1995;  131 239-250
    CrossrefPubMedGoogle Scholar
      >