S. Nagano et al., Reduction of metallothioneins promotes the disease expression of familial amyotrophic lateral sclerosis mice in a dose-dependent manner, EUR J NEURO, 13(7), 2001, pp. 1363-1370
We previously reported that abnormal copper release from mutated Cu, Zn-sup
eroxide 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 prese
nt study, we first examined metallothioneins (MTs), known to bind copper io
ns 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 (G9
3A), 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 an
d death significantly earlier in response to the reduction of protein expre
ssion. These results indicated that the copper-mediated free radical genera
tion 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 expr
ession of the disease.