Reduction of metallothioneins promotes the disease expression of familial amyotrophic lateral sclerosis mice in a dose-dependent manner.

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.