The genetic and molecular mechanisms of motor neuron disease

Current Opinion in Neurobiology

Volumn 8, Issue 6, 1998, Pages 791-799

  Wong, Philip C ^a   Rothstein, Jeffrey D ^b   Price, Donald L ^b  

^a Division of Neuropathology   (United States)

^b Neuroscience Branch   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

EXCITOTOXIN; SUPEROXIDE DISMUTASE;

CLINICAL FEATURE; GENE ISOLATION; GENE TARGETING; HUMAN; MOTOR NEURON DISEASE; PRIORITY JOURNAL; REVIEW; SPASTIC PARAPLEGIA; SPINAL MUSCULAR ATROPHY; TRANSGENIC MOUSE;

EID: 0031672857     PISSN: 09594388     EISSN: None     Source Type: Journal    
DOI: 10.1016/S0959-4388(98)80123-2     Document Type: Article

References (84)

1. Rowland LP. Natural history and clinical features of amyotrophic lateral sclerosis and related motor neuron diseases. Calne DB. Neurodegenerative Diseases. 1994;507-521 WB Saunders, Philadelphia.
2. Kato T, Katagiri T, Hirano A, Kawanami T, Sasaki H. Lewy body-like hyaline inclusions in sporadic motor neuron disease are ubiquitinated. Acta Neuropathol. 77:1989;391-396.
3. Takahashi H, Oyanagi K, Ohama E, Ikuta F. Clarke's column in sporadic amyotrophic lateral sclerosis. Acta Neuropathol. 84:1992;465-470.
4. Bradley WG, Good P, Rasool CG, Adelman LS. Morphometric and biochemical studies of peripheral nerves in amyotrophic lateral sclerosis. Ann Neurol. 14:1983;267-277.
5. Lowe J. New pathological findings in amyotrophic lateral sclerosis. J Neurol Sci. 124:1994;38-51.
6. Price DL, Borchelt DR, Wong PC, Pardo CA, Thinakaran G, Lee MK, Cleveland DW, Sisodia SS. Neurodegenerative diseases and model systems. Cold Spring Harb Symp Quant Biol. LVI:1996;725-738.
7. Ghadge GD, Lee JP, Bindokas VP, Jordan J, Ma L, Miller RJ, Roos RP. Mutant superoxide dismutase-1-linked familial amyotrophic lateral sclerosis: molecular mechanisms of neuronal death and protection. of special interest J Neurosci. 17:1997;8756-8766 This in vitro study used replication-deficient recombinant adenoviruses to introduce wild-type or mutant SOD1 into several different cell lines. In these systems, dying cells show features of apoptosis. The authors were able to attenuate cell death using copper chelators, Bcl2, and inhibitors of caspases.
8. Julien J-P. Neurofilaments and motor neuron disease. Trends Cell Biol. 7:1997;243-249.
9. Hentati A, Bejaoui K, Pericak-Vance MA, Hentati F, Speer MC, Hung W-Y, Figlewicz DA, Haines J, Rimmler J, Hamida CB, et al. Linkage of recessive familial amyotrophic lateral sclerosis to chromosome 2q33-q35. Nat Genet. 7:1994;425-428.
10. Brown RH Jr. Amyotrophic lateral sclerosis. Insights from genetics. Arch Neurol. 54:1997;1246-1250.
11. Rosen DR, Siddique T, Patterson D, Figlewicz DA, Sapp P, Hentati A, Donaldson D, Goto J, O'Regan JP, Deng H-X, et al. Mutations in Cu/Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis. Nature. 362:1993;59-62.
12. Deng H-X, Hentati A, Tainer JA, Iqbal Z, Cayabyab A, Hung W-Y, Getzoff ED, Hu P, Herzfeldt B, Roos RP, et al. Amyotrophic lateral sclerosis and structural defects in Cu,Zn superoxide dismutase. Science. 261:1993;1047-1051.
13. Cudkowicz ME, McKenna-Yasek D, Chen C, Hedley-Whyte ET, Brown RH Jr. Limited corticospinal tract involvement in amyotrophic lateral sclerosis subjects with the A4V mutation in the copper/zinc superoxide dismutase gene. of outstanding interest Ann Neurol. 43:1998;703-710 This comprehensive study documents the genotypes/phenotypes of 112 families with dominantly inherited ALS and reports SOD1 mutations in 68 families. The results indicate allelic heterogeneity in cases with SOD mutations.
14. Chance PF, Rabin BA, Ryan SG, Ding Y, Scavina M, Crain B, Griffin JW, Cornblath DR. Linkage of the gene for an autosomal dominant form of juvenile amyotrophic lateral sclerosis to chromosome 9q34. Am J Hum Genet. 62:1998;633-640.
15. Figlewicz DA, Krizus A, Martinoli MG, Meininger V, Dib M, Rouleau GA, Julien J-P. Variants of the heavy neurofilament subunit are associated with the development of amyotrophic lateral sclerosis. Hum Mol Genet. 3:1994;1757-1761.
16. Rooke K, Figlewicz DA, Han F-Y, Rouleau GA. Analysis of the KSP repeat of the neurofilament heavy subunit in familial amyotrophic lateral sclerosis. Neurology. 46:1996;789-790.
17. Vechio JD, Bruijn LI, Xu Z, Brown RH Jr, Cleveland DW. Sequence variants in human neurofilament proteins: absence of linkage to familial amyotrophic lateral sclerosis. Ann Neurol. 40:1996;603-610.
18. Hong S, Brooks BR, Hung WY, Siddique NA, Rimmler J, Fan C, Kaplan JP, Deng HX, Reyes RK, Brown RH Jr, et al. X-linked dominant locus for late-onset familial amyotrophic lateral sclerosis. Soc Neurosci Abstr. 24:1998;478.
19. Gurney ME, Pu H, Chiu AY, Dal Canto MC, Polchow CY, Alexander DD, Caliendo J, Hentati A, Kwon YW, Deng H-X, Chen W, et al. Motor neuron degeneration in mice that express a human Cu,Zn superoxide dismutase mutation. Science. 264:1994;1772-1775.
20. Chiu AY, Zhai P, Dal Canto MC, Peters TM, Kwon YW, Prattis SM, Gurney ME. Age-dependent penetrance of disease in a transgenic mouse model of familial amyotrophic lateral sclerosis. Mol Cell Neurosci. 6:1995;349-362.
21. Mourelatos Z, Gonatas NK, Stieber A, Gurney ME, Dal Canto MC. The Golgi apparatus of spinal cord motor neurons in transgenic mice expressing mutant Cu,Zn superoxide dismutase becomes fragmented in early, preclinical stages of the disease. Proc Natl Acad Sci USA. 93:1996;5472-5477.
22. Dal Canto MC, Gurney ME. Development of central nervous system pathology in a murine transgenic model of human amyotrophic lateral sclerosis. Am J Pathol. 145:1994;1271-1280.
23. Kong J, Xu Z. Massive mitochondrial degeneration in motor neurons triggers the onset of amyotrophic lateral sclerosis in mice expressing a mutant SOD1. of special interest J Neurosci. 18:1997;3241-3250 This paper details the time course of damage to mitochondria in G93A transgenic mice and relates these findings to the clinical stages of ALS.
24. Tu P-H, Raju P, Robinson KA, Gurney ME, Trojanowski JQ, Lee VMY. Transgenic mice carrying a human mutant superoxide dismutase transgene develop neuronal cytoskeletal pathology resembling human amyotrophic lateral sclerosis lesions. Proc Natl Acad Sci USA. 93:1996;3155-3160.
25. Zhang B, Tu P-H, Abtahian F, Trojanowski JQ, Lee VMY. Neurofilaments and orthograde transport are reduced in ventral root axons of transgenic mice that express human SOD1 with a G93A mutation. of special interest J Cell Biol. 139:1997;1307-1315 The authors used quantitative western blots to measure the level of NFs in the motor roots of SOD1 transgenic G93A mice and found that it decreases progressively. Both fast and slow axonal transports are impaired in the motor roots.
26. Dal Canto MC, Gurney ME. A low expressor line of transgenic mice carrying a mutant human Cu,Zn superoxide dismutase (SOD1) gene develops pathological changes that most closely resemble those in human amyotrophic lateral sclerosis. Acta Neuropathol. 93:1997;537-550.
27. Gurney ME, Cuttings FB, Zhai P, Doble A, Taylor CP, Andrus PK, Hall ED. Benefit of vitamin E, riluzole, and gabapentin in a transgenic model of familial amyotrophic lateral sclerosis. Ann Neurol. 39:1996;147-157.
28. Hottinger AF, Fine EG, Gurney ME, Zurn AD, Aebischer P. The copper chelator d-penicillamine delays onset of disease and extends survival in a transgenic mouse model of familial amyotrophic lateral sclerosis. Eur J Neurosci. 9:1997;1548-1551.
29. 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. 277:1997;559-562 This is a first study to show that overexpression of Bcl-2 delays the onset of motor neuron disease and prolongs survival in G93A transgenic mice, implying it plays a role in cell death pathways in FALS.
30. Friedlander RM, Brown RH, Gagliardini V, Wang J, Yuan J. Inhibition of ICE slows ALS in mice. Nature. 388:1997;31.
31. Wong 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. 14:1995;1105-1116.
32. Borchelt DR, Wong PC, Becher MW, Pardo CA, Lee MK, Xu Z-S, Thinakaran G, Jenkins NA, Copeland NG, Sisodia SS, et al. Axonal transport of mutant superoxide dismutase 1 and focal axonal abnormalities in the proximal axons of transgenic mice. of special interest Neurobiol Dis. 5:1998;27-35 This immunocytochemical study shows that SOD1 accumulates locally in the enlarged motor axons of G37R SOD1 mutant mice. These axonal abnormalities are an early event, occurring significantly before the onset of clinical signs. Metabolic labeling methods demonstrated that the mutant protein, as well as the endogenous mouse SOD1, are transported anterograde in the slow component of axonal transport.
33. Eyer J, Peterson A. Neurofilament-deficient axons and perikaryal aggregates in viable transgenic mice expressing a neurofilament-β-galactosidase fusion protein. Neuron. 12:1994;389-405.
34. Côté F, Collard J-F, Julien J-P. Progressive neuronopathy in transgenic mice expressing the human neurofilament heavy gene: a mouse model of amyotrophic lateral sclerosis. Cell. 73:1993;35-46.
35. Eyer J, Cleveland DW, Wong PC, Peterson AC. Pathogenesis of two axonopathies does not require axonal neurofilaments. of outstanding interest Nature. 391:1998;584-587 This is a first study designed to test the role of NFs in disease pathogenesis using a genetic approach whereby two neurodegenerative disease models (dystonia musculorum and SOD1-linked FALS) are placed into a stain background such that NFs are excluded from the axons. No significant influence on disease onset or progression was observed in either case, suggesting that an axonal NF-containing cytoskeleton does not play a major pathogenic role in these two models.
36. Couillard-Després S, Zhu Q, Wong PC, Price DL, Cleveland DW, Julien J-P. Protective effect of neurofilament NF-H overexpression in motor neuron disease induced by mutant superoxide dismutase. of outstanding interest Proc Natl Acad Sci USA. 95:1998;9626-9630 Expression of wild-type human NF-H in the G37R SOD1 transgenic mice increases the mean life-span and attenuates the cellular phenotype in these animals. It appears that the NF-H gene exerts the most robust protective effect in SOD1 models of FALS.
37. Bruijn 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. of outstanding interest Neuron. 18:1997;327-338 The clinical and cellular phenotypes of several lines of G85R mice are detailed. The Lewy-body-like inclusions in astrocytes resemble those occurring in a Japanese ALS family with a frameshift mutation (see [38]).
38. Kato S, Shimoda M, Watanabe Y, Nakashima K, Takahashi K, Ohama E. Familial amyotrophic lateral sclerosis with a two base pair deletion in superoxide dismutase 1 gene: multisystem degeneration with intracytoplasmic hyaline inclusions in astrocytes. J Neuropathol Exp Neurol. 55:1996;1089-1101.
39. Williamson TL, Bruijn LI, Zhu Q, Anderson KL, Anderson SD, Julien J-P, Cleveland DW. Absence of neurofilaments reduces the selective vulnerability of motor neurons and slows disease caused by a familial amyotrophic lateral sclerosis-linked superoxide dismutase 1 mutant. Proc Natl Acad Sci USA. 95:1998;9631-9636.
40. Bruijn 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. 281:1998;1851-1854 This report documents that either elimination or increased expression of wild-type SOD1 has no influence on disease onset or progression in G85R SOD1 transgenic mice. These data were interpreted to be inconsistent with the view that neurotoxicity in FALS is caused by superoxide-mediated oxidative stress. The authors propose that the SOD1-immunoreactive intracellular aggregates observed in the G85R SOD1 transgenic mice are critical in mediating neurotoxicity via co-aggregation of mutant SOD1 with another key molecule(s).
41. Ripps ME, Huntley GW, Hof PR, Morrison JH, Gordon JW. Transgenic mice expressing an altered murine superoxide dismutase gene provide an animal model of amyotrophic lateral sclerosis. Proc Natl Acad Sci USA. 92:1995;689-693.
42. Morrison BM, Janssen WG, Gordon JW, Morrison JH. Time course of neuropathology in the spinal cord of G86R superoxide dismutase transgenic mice. J Comp Neurol. 391:1998;64-77.
43. Morrison BM, Janssen WG, Gordon JW, Morrison JH. Quantitative immunocytochemical analysis of the spinal cord in G86R superoxide dismutase transgenic mice: neurochemical correlates of selective vulnerability. J Comp Neurol. 373:1996;619-631.
44. Borchelt DR, Lee MK, Slunt HH, Guarnieri M, Xu Z-S, Wong PC, Brown RH Jr, Price DL, Sisodia SS, Cleveland DW. Superoxide dismutase 1 with mutations linked to familial amyotrophic lateral sclerosis possesses significant activity. Proc Natl Acad Sci USA. 91:1994;8292-8296.
45. Borchelt DR, Guarnieri M, Wong PC, Lee MK, Slunt HS, Xu Z-S, Sisodia SS, Price DL, Cleveland DW. Superoxide dismutase 1 subunits with mutations linked to familial amyotrophic lateral sclerosis do not affect wild-type subunit function. J Biol Chem. 270:1995;3234-3238.
46. Rabizadeh S, Butler Gralla E, Borchelt DR, Gwinn R, Selverstone Valentine J, Sisodia S, Wong P, Lee M, Hahn H, Bredesen DE. 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. 92:1995;3024-3028.
47. Wiedau-Pazos M, Goto JJ, Rabizadeh S, Gralla EB, Roe JA, Lee MK, Valentine JS, Bredesen DE. Altered reactivity of superoxide dismutase in familial amyotrophic lateral sclerosis. Science. 271:1996;515-518.
48. Reaume AG, Elliott JL, Hoffman EK, Kowall NW, Ferrante RJ, Siwek DF, Wilcox HM, Flood DG, Beal MF, Brown RH Jr, et al. Motor neurons in Cu/Zn superoxide dismutase-deficient mice develop normally but exhibit enhanced cell death after axonal injury. Nat Genet. 13:1996;43-47.
49. Beckman JS, Carson M, Smith CD, Koppenol WH. ALS, SOD and peroxynitrite. Nature. 364:1993;584.
50. Crow JP, Sampson JB, Zhuang Y, Thompson JA, Beckman JS. Decreased zinc affinity of amyotrophic lateral sclerosis-associated superoxide dismutase mutants leads to enhanced catalysis of tyrosine nitration by peroxynitrite. of special interest J Neurochem. 69:1997;1936-1944 This report shows for the first time that several FALS-linked SOD1 mutants possess marked reduction in their ability to bind zinc, resulting in an increase in the mutants' ability to catalyze peroxynitrite-mediated tyrosine nitration. This suggests that mutant SOD1 without zinc may play an important pathogenic role in SOD1-linked FALS.
51. Beal MF, Ferrante RJ, Browne SE, Matthews RT, Kowall NW, Brown RH Jr. Increased 3-nitrotyrosine in both sporadic and familial amyotrophic lateral sclerosis. of special interest Ann Neurol. 42:1997;646-654 This report provides evidence that peroxynitrite-mediated tyrosine nitration is present in neuronal tissue from cases of sporadic and familial ALS.
52. Bruijn LI, Beal MF, Becher MW, Schulz JB, Wong PC, Price DL, Cleveland DW. 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. of special interest Proc Natl Acad Sci USA. 94:1997;7606-7611 This is the first study to report that free nitrotyrosine levels are increased in a mutant SOD1 transgenic model of ALS.
53. 8dG.
54. Harris ZL, Gitlin JD. Genetic and molecular basis for copper toxicity. Am J Clin Nutr. 63:1996;836S-841S.
55. Pufahl RA, Singer CP, Peariso KL, Lin S-J, Schmidt PJ, Fahrni CJ, Culotta VC, Penner-Hahn JE, O'Halloran TV. Metal ion chaperone function of the soluble Cu(I) receptor Atx1. Science. 278:1997;853-856.
56. Valentine JS, Gralla EB. Delivering copper inside yeast and human cells. Science. 278:1997;817-818.
57. Culotta VC, Klomp LWJ, Strain J, Casareno RLB, Krems B, Gitlin GD. The copper chaperone for superoxide dismutase. of outstanding interest J Biol Chem. 272:1997;23469-23472 The initial description of Lys7 and its mammalian homologue CCS, both of which serve as intracellular copper chaperones for SOD1. The discovery of CCS provides an opportunity to examine the role of copper in SOD1-linked FALS.
58. Rothstein JD, Dykes-Hoberg M, Corson LB, Becher M, Cleveland DW, Price DL, Culotta VC, Wong PC. The copper chaperone CCS is abundant in neurons and astrocytes in human and rodent brain. of special interest J Neurochem. 1998; This is the first study to report the co-localization of CCS and SOD1 to spinal motor neurons, implicating the importance of CCS in mutant SOD1-linked FALS.
59. Casareno RLB, Waggoner D, Gitlin JD. The copper chaperone CCS directly interacts with copper/zinc superoxide dismutase. of special interest J Biol Chem. 273:1998;23625-23628 This report documents for the first time biochemical evidence that CCS interact directly with wild-type and FALS-linked mutant SOD1, and it proposes a pathogenic mechanism for SOD1-linked FALS.
60. Corson LB, Culotta VC, Cleveland DW. Chaperone-facilitated copper binding is a property common to several classes of familial amyotrophic lateral sclerosis-linked superoxide dismutase mutants. of special interest Proc Natl Acad Sci USA. 95:1998;6361-6366 This is the first study to show that FALS-linked mutant SOD1 acquires copper in vivo through the intracellular metal chaperone CCS.
61. Leigh PN, Meldrum BS. Excitotoxicity in ALS. Neurology. 47:1996;S221-S227.
62. Rothstein JD. Excitotoxicity hypothesis. Neurology. 47:1996;S19-S26.
63. Rothstein JD, Van Kammen M, Levey AI, Martin LJ, Kuncl RW. Selective loss of glial glutamate transporter GLT-1 in amyotrophic lateral sclerosis. Ann Neurol. 38:1995;73-84.
64. Rothstein JD, Tsai G, Kuncl RW, Clawson L, Cornblath DR, Drachman DB, Pestronk A, Stauch BL, Coyle JT. Abnormal excitatory amino acid metabolism in amyotrophic lateral sclerosis. Ann Neurol. 28:1990;18-25.
65. Lin CL, Bristol LA, Jin L, Dykes-Hoberg M, Crawford T, Clawson L, Rothstein JD. Aberrant RNA processing in neurodegenerative disease: the cause for absent EAAT2, a glutamate transporter, in amyotrophic lateral sclerosis. of outstanding interest Neuron. 20:1998;589-602 The first demonstration of aberrant RNA splicing products and an abnormal splicing mechanism in a human neurological disease.
66. Bai G, Lipton SA. Aberrant RNA splicing in sporadic amyotrophic lateral sclerosis. of special interest Neuron. 20:1998;363-366 This review places the finding of aberrant RNA splicing in ALS into perspective.
67. of special interest Grabowski PJ. Splicing regulation in neurons: tinkering with cell-specific control. of special interest Cell. 92:1998;709-712 This review places the observation by Lin et al. [65] in the context of controlled splicing in nerve cells and the implication for understanding disease mechanisms.
68. Rothstein JD, Dykes-Hoberg M, Pardo CA, Bristol LA, Jin L, Kuncl RW, Kanai Y, Hediger MA, Wang Y, Schielke J, Welty DF. Antisense knockout of glutamate transporters reveals a predominant role for astroglial glutamate transport in excitotoxicity and clearance of extracellular glutamate. Neuron. 16:1996;675-686.
69. Casari G, Defusco M, Ciarmatori S, Zeviani M, Mora M, Fernandez P, De Michele G, Filla A, Cocozza S, Marconi R, et al. Spastic paraplegia and OXPHOS impairment caused by mutations in paraplegin, a nuclear-encoded mitochondrial metalloprotease. Cell. 93:1998;973-983 This is a first report to identify subsets of autosomal-recessive HSP cases linked to a deletion in paraplegin, a nuclear-encoded metalloprotease localized to mitochondria.
70. Hentati A, Pericak-Vance MA, Lennon F, Wasserman B, Hentati F, Juneja T, Angrist MH, Hung W-Y, Boustany R-M, Bohlega S, et al. Linkage of a locus for autosomal dominant familial spastic paraplegia to chromosome 2p markers. Hum Mol Genet. 3:1994;1867-1871.
71. Fink JK. Advances in hereditary spastic paraplegia. Curr Opin Neurol. 10:1997;313-318.
72. Reid E. Pure hereditary spastic paraplegia. J Med Genet. 34:1997;499-503.
73. Hentati A, Pericak-Vance MA, Hung W-Y, Belal S, Laing N, Boustany R-M, Hentati F, Hamida MB, Siddique T. Linkage of 'pure' autosomal recessive familial spastic paraplegia to chromosome 8 markers and evidence of genetic locus heterogeneity. Hum Mol Genet. 3:1994;1263-1267.
74. Crawford T, Pardo CA. The neurobiology of childhood spinal muscular atrophy. Neurobiol Dis. 3:1996;97-110.
75. Lefebvre S, Bürglen L, Reboullet S, Clermont O, Burlet P, Viollet L, Benichou B, Cruaud C, Millasseau P, Zeviani M, et al. Identification and characterization of a spinal muscular atrophy-determining gene. Cell. 80:1995;155-165.
76. Roy N, Mahadevan MS, Mclean M, Shutler G, Yaraghi Z, Farahani R, Baird S, Besner-Johnston A, Lefebvre C, Kang X, et al. The gene for neuronal apoptosis inhibitory protein is partially deleted in individuals with spinal muscular atrophy. Cell. 80:1995;167-178.
77. Bergin A, Kim G, Price DL, Sisodia SS, Lee MK, Rabin BA. Identification and characterization of a mouse homologue of the spinal muscular atrophy-determining gene, survival motor neuron. Gene. 204:1997;47-53.
78. Didonato CJ, Ingraham SE, Mendell JR, Prior TW, Lenard S, Moxley RTI, Florence J, Burghes AHM. Deletion and conversion in spinal muscular atrophy patients: is there a relationship to severity? Ann Neurol. 41:1997;230-237.
79. Lefebvre S, Burlet P, Liu Q, Bertrandy S, Clermont O, Munnich A, Dreyfuss G, Melki J. Correlation between severity and SMN protein level in spinal muscular atrophy. of special interest Nat Genet. 16:1997;265-269 This is a first patient study of a large cohort (52 cases) of SMA individuals to correlate the levels of SMN protein encoded by the SMNc gene and the clinical manifestations of the disease; individuals with SMA have a marked deficiency of SMN protein. The results of this study suggest that SMA is caused by an aberrant expression of SMN protein.
80. Schrank B, Götz R, Gunnersen JM, Ure JM, Toyka KV, Smith AG, Sendtner M. Inactivation of the survival motor neuron gene, a candidate gene for human spinal muscular atrophy, leads to massive cell death in early mouse embryos. of special interest Proc Natl Acad Sci USA. 94:1997;9920-9925 This report shows for the first time that homozygous disruption of the SMN gene is associated with massive cell death during early embryonic development, demonstrating that SMN is essential for cell survival and function. The phenotypic differences observed between the loss of SMN in mouse and human can be attributed to gene copy number as there is only a single SMN gene in mice but two SMN genes in humans.
81. Dreyfuss G, Hentze M, Lamond AI. From transcript to protein. Cell. 85:1996;963-972.
82. Liu Q, Fischer U, Wang F, Dreyfuss G. The spinal muscular atrophy disease gene product, SMN, and its associated protein SIP1 are in a complex with spliceosomal snRNP proteins. of outstanding interest Cell. 90:1997;1013-1021 This paper reports for the first time the association of SMN with a novel protein, SIP1, as part of a specific complex with several spliceosomal snRNP proteins. These findings suggest that SMA is probably caused by perturbation of spliceosomal snRNP function.
83. Liston P, Roy N, Tamai K, Lefebvre C, Baird S, Cherton-Horvat G, Farahani R, Mclean M, Ikeda J-E, Mackenzie A, Korneluk RG. Suppression of apoptosis in mammalian cells by NAIP and a related family of IAP genes. Nature. 379:1996;349-353.
84. Liu Q, Dreyfuss G. A novel nuclear structure containing the survival of motor neurons protein. EMBO J. 15:1996;3555-3565.