Misfolded CuZnSOD and amyotrophic lateral sclerosis.
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TLDR
Some of the properties of both wild-type and mutant CuZnSOD proteins are reviewed, suggests how these properties may be relevant to these two hypotheses, and proposes that these two hypothesis are not necessarily mutually exclusive.Abstract:
Amyotrophic lateral sclerosis (ALS) is a progressive degenerative disease of motor neurons. The inherited form of the disease, familial ALS, represents 5–10% of the total cases, and the best documented of these are due to lesions in SOD1, the gene encoding copper–zinc superoxide dismutase (CuZnSOD). The mechanism by which mutations in SOD1 cause familial ALS is currently unknown. Two hypotheses have dominated recent discussion of the toxicity of ALS mutant CuZnSOD proteins: the oligomerization hypothesis and the oxidative damage hypothesis. The oligomerization hypothesis maintains that mutant CuZnSOD proteins are, or become, misfolded and consequently oligomerize into increasingly high-molecular-weight species that ultimately lead to the death of motor neurons. The oxidative damage hypothesis maintains that ALS mutant CuZnSOD proteins catalyze oxidative reactions that damage substrates critical for viability of the affected cells. This perspective reviews some of the properties of both wild-type and mutant CuZnSOD proteins, suggests how these properties may be relevant to these two hypotheses, and proposes that these two hypotheses are not necessarily mutually exclusive.read more
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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
Aggresomes: A Cellular Response to Misfolded Proteins
TL;DR: The intracellular fate of cystic fibrosis transmembrane conductance regulator (CFTR) is investigated and it is demonstrated that undegraded CFTR molecules accumulate at a distinct pericentriolar structure which is termed the aggresome.
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.