title: Reduction of metallothioneins promotes the disease expression of familial amyotrophic lateral sclerosis mice in a dose-dependent manner.
abstract: 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.
authors: Department of Neurology, Osaka University Graduate School of Medicine, 2-2 Yamadaoka Suita, Osaka 565-0871, Japan.
authors: S
authors: S
authors: Nagano
authors: M
authors: M
authors: Satoh
authors: H
authors: H
authors: Sumi
authors: H
authors: H
authors: Fujimura
authors: C
authors: C
authors: Tohyama
authors: T
authors: T
authors: Yanagihara
authors: S
authors: S
authors: Sakoda
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D003300:Copper / Q000378:metabolism; D004195:Disease Models, Animal; D018628:Gene Dosage; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D017665:Hydroxyl Radical / Q000378:metabolism; D008668:Metallothionein / Q000235:genetics* / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008813:Mice, Inbred ICR; D008822:Mice, Transgenic; D018384:Oxidative Stress / Q000502:physiology; D013116:Spinal Cord / Q000378:metabolism / Q000473:pathology; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism
chemical_list: D017665:Hydroxyl Radical; D003300:Copper; D008668:Metallothionein; D013482:Superoxide Dismutase