Up-regulation of protein chaperones preserves viability of cells expressing toxic Cu/Zn-superoxide dismutase mutants associated with amyotrophic lateral sclerosis

Mutations in the Cu/Zn-superoxide dismutase (SOD-I) gene underlie some fami lial cases of amyotrophic lateral sclerosis, a neurodegenerative disorder c haracterized by loss of cortical, brainstem, and spinal motor neurons, We p resent evidence that SOD-1 mutants alter the activity of molecular chaperon es that aid in proper protein folding and targeting of abnormal proteins fo r degradation. In a cultured cell line (NIH 3T3), resistance to mutant SOD- 1 toxicity correlated with increased overall chaperoning activity (measured by the ability of cytosolic extracts to prevent heat denaturation of catal ase) as well as with upregulation of individual chaperones/stress proteins, in transgenic mice expressing human SOD-1 with the G93A mutation, chaperon ing activity was decreased in lumbar spinal cord but increased or unchanged in clinically unaffected tissues. Increasing the level of the stress-induc ible chaperone 70-kDa heat shock protein by gene transfer reduced formation of mutant SOD-containing proteinaceous aggregates in cultured primary moto r neurons expressing G93A SOD-1 and prolonged their survival, We propose th at insufficiency of molecular chaperones may be directly involved in loss o f motor neurons in this disease.