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Reduction of metallothioneins promotes the disease expression of familial amyotrophic lateral sclerosis mice in a dose‐dependent manner
Author(s) -
Nagano Seiichi,
Satoh Masahiko,
Sumi Hisae,
Fujimura Harutoshi,
Tohyama Chiharu,
Yanagihara Takehiko,
Sakoda Saburo
Publication year - 2001
Publication title -
european journal of neuroscience
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.346
H-Index - 206
eISSN - 1460-9568
pISSN - 0953-816X
DOI - 10.1046/j.0953-816x.2001.01512.x
Subject(s) - sod1 , amyotrophic lateral sclerosis , genetically modified mouse , pathogenesis , spinal cord , transgene , superoxide dismutase , mutation , oxidative stress , biology , microbiology and biotechnology , chemistry , immunology , disease , pathology , medicine , endocrinology , gene , neuroscience , genetics
We previously reported that abnormal copper release from mutated Cu, Zn‐superoxide dismutase (SOD1) proteins might be a common toxic gain‐of‐function in the pathogenesis of familial amyotrophic lateral sclerosis (FALS) [Ogawa et al . (1997) Biochem. Biophys. Res. Commun. , 241 , 251–257.]. In the present study, we first examined metallothioneins (MTs), known to bind copper ions and decrease oxidative toxicity, and found a twofold increase in MTs in the spinal cord of the SOD1 transgenic mice with a FALS‐linked mutation (G93A), but not in the spinal cord of wild‐type SOD1 transgenic mice. We then investigated whether the clinical course of FALS mice could be modified by the reduced expression of MTs, by crossing the FALS mice with MT‐I‐ and MT‐II‐deficient mice. FALS mice clearly reached the onset of clinical signs and death significantly earlier in response to the reduction of protein expression. These results indicated that the copper‐mediated free radical generation derived from mutant SOD1 might be related to the degeneration of motor neurons in FALS and that MTs might play a protective role against the expression of the disease.