Genetics of amyotrophic lateral sclerosis.
Teepu Siddique,Han Xiang Deng +1 more
TLDR
Investigations suggest that mutant SOD1 acts through a toxic gain of function which may involve generation of free radicals and to the pathogenesis of ALS.Abstract:
Amyotrophic lateral sclerosis (ALS) is a paralytic disorder caused by degeneration of motor neurons in the brain and spinal cord. Identification of mutations in the gene for Cu,Zn superoxide dismutase (SOD1) in a subset of ALS families made it possible to develop a transgenic mouse model of ALS and to investigate its pathogenesis. These investigations suggest that mutant SOD1 acts through a toxic gain of function which may involve generation of free radicals. Conformational change in the mutant SOD1 protein, especially the distortion of the 'rim' of the electrostatic guidance channel may be central to this toxic gain of function and to the pathogenesis of ALS.read more
Citations
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Journal ArticleDOI
Aberrant RNA processing in a neurodegenerative disease: the cause for absent EAAT2, a glutamate transporter, in amyotrophic lateral sclerosis.
Chien Liang Glenn Lin,Lynn A. Bristol,Lin Jin,Margaret Dykes-Hoberg,Thomas O. Crawford,Lora Clawson,Jeffrey D. Rothstein +6 more
TL;DR: It is suggested that the loss of EAAT2 in ALS is due to aberrant mRNA and that these aberrant mRNAs could result from RNA processing errors, and could be important in the pathophysiology of neurodegenerative disease and in excitotoxicity.
Journal ArticleDOI
Transgenics, toxicity and therapeutics in rodent models of mutant SOD1-mediated familial ALS.
TL;DR: mounting evidence from mice with cell restrictive, repressible or chimeric expression of mutant SOD1 transgenes and bone marrow transplants supports non-neuronal origins of neuroprotection in ALS.
Journal ArticleDOI
The structural biochemistry of the superoxide dismutases
TL;DR: The current understanding of how Cu,ZnSOD mutations may lead to aggregation/fibril formation is described, as a detailed understanding of these mechanisms provides new avenues for the development of therapeutics against this so far untreatable neurodegenerative pathology.
Journal ArticleDOI
Identification and Functional Expression of HAH1, a Novel Human Gene Involved in Copper Homeostasis
Leo W.J. Klomp,Su Ju Lin,Daniel S. Yuan,Richard D. Klausner,Valeria C. Culotta,Jonathan D. Gitlin +5 more
TL;DR: Yeast strains lacking ATX1 are deficient in high affinity iron uptake and expression of HAH1 in these strains permits growth on iron-depleted media and results in restoration of copper incorporation into newly synthesized Fet3p.
Journal ArticleDOI
SOD1 mutants linked to amyotrophic lateral sclerosis selectively inactivate a glial glutamate transporter
TL;DR: It is proposed that toxic properties of S OD1 mutants lead to neuronal death via an excitotoxic mechanism in SOD1-linked FALS through oxidative reactions triggered by hydrogen peroxide and catalyzed by A4V and I113T mutant but not wild-type SOD 1 inactivated the glutamate transporter human GLT1.
References
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Journal ArticleDOI
Mutations in Cu/Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis
TL;DR: Tight genetic linkage between FALS and a gene that encodes a cytosolic, Cu/Zn-binding superoxide dismutase (SOD1), a homodimeric metalloenzyme that catalyzes the dismutation of the toxic superoxide anion O–2 to O2 and H2O2 is reported.
Journal ArticleDOI
Motor neuron degeneration in mice that express a human Cu,Zn superoxide dismutase mutation.
Mark E. Gurney,Haifeng Pu,Arlene Y. Chiu,Mauro C. Dal Canto,Cynthia Y. Polchow,Denise D. Alexander,Jan Caliendo,Afif Hentati,Young W. Kwon,Han Xiang Deng,W. Chen,Ping Zhai,Robert L. Sufit,Teepu Siddique +13 more
TL;DR: In this article, the authors found that mutations of human Cu,Zn superoxide dismutase (SOD) contribute to the pathogenesis of familial amyotrophic lateral sclerosis (ALS).
Journal ArticleDOI
An adverse property of a familial ALS-linked SOD1 mutation causes motor neuron disease characterized by vacuolar degeneration of mitochondria
Philip C. Wong,Carlos A. Pardo,David R. Borchelt,Michael K. Lee,Neal G. Copeland,Nancy A. Jenkins,Sangram S. Sisodia,Don W. Cleveland,Don W. Cleveland,Donald L. Price +9 more
TL;DR: Mutations in Cu/Zn superoxide dismutase cause a subset of cases of familial amyotrophic lateral sclerosis, and four lines of mice accumulating one of these mutant proteins (G37R) develop severe, progressive motor neuron disease.
Journal ArticleDOI
Amyotrophic lateral sclerosis and structural defects in Cu,Zn superoxide dismutase
Han Xiang Deng,Afif Hentati,John A. Tainer,Zafar Iqbal,Annarueber Cayabyab,Wu Yen Hung,Elizabeth D. Getzoff,Ping Hu,Brian Herzfeldt,Raymond P. Roos,Carolyn Warner,Gang Deng,Edwin Soriano,Celestine Smyth,Hans E. Parge,Aftab Ahmed,Allen D. Roses,Robert A. Hallewell,Margaret A. Pericak-Vance,Teepu Siddique +19 more
TL;DR: In this article, single-site mutants in the Cu,Zn superoxide dismutase (SOD) gene occur in patients with the fatal neurodegenerative disorder familial amyotrophic lateral sclerosis.
Journal ArticleDOI
Motor neurons in Cu/Zn superoxide dismutase-deficient mice develop normally but exhibit enhanced cell death after axonal injury.
Andrew G. Reaume,Jeffrey L. Elliott,Eric K. Hoffman,Neil W. Kowall,Neil W. Kowall,Robert J. Ferrante,Robert J. Ferrante,Donald R Siwek,Donald R Siwek,Heide M. Wilcox,Dorothy G. Flood,M. Flint Beal,Robert H. Brown,Richard W. Scott,William D. Snider +14 more
TL;DR: The creation and characterization of mice completely deficient for SOD1 indicate that Cu/Zn SOD is not necessary for normal motor neuron development and function but is required under physiologically stressful conditions following injury.
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