Up-regulation of protein chaperones preserves viability of cells expressing toxic Cu/Zn-superoxide dismutase mutants associated with amyotrophic lateral sclerosis
W. Bruening et al., Up-regulation of protein chaperones preserves viability of cells expressing toxic Cu/Zn-superoxide dismutase mutants associated with amyotrophic lateral sclerosis, J NEUROCHEM, 72(2), 1999, pp. 693-699
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.