Calcineurin activity is regulated both by redox compounds and by mutant familial amyotrophic lateral sclerosis-superoxide dismutase.
Calcineurin (CN) is a protein phosphatase involved in a wide range of cellular responses to calcium-mobilizing signals, and a role for this enzyme in neuropathology has been postulated. We have investigated the possibility that redox modulation of CN activity is relevant to neuropathological conditions where an imbalance in reactive oxygen species has been described. We have monitored CN activity in cultured human neuroblastoma SH-SY5Y cells and obtained evidence that CN activity is promoted by treatment with ascorbate or dithiothreitol and impaired by oxidative stress. Evidence for the existence of a redox regulation of this enzyme has been also obtained by overexpression of wild-type antioxidant Cu,Zn superoxide dismutase (SOD1) that promotes CN activity and protects it from oxidative inactivation. On the contrary, overexpression of mutant SOD1s associated with familial amyotrophic lateral sclerosis (FALS) impairs CN activity both in transfected human neuroblastoma cell lines and in the motor cortex of brain from FALS-transgenic mice. These data suggest that CN might be a target in the pathogenesis of SOD1-linked FALS.
Ferri
A
A
Fondazione S. Lucia IRCCS, Roma, Italy.
Gabbianelli
R
R
Casciati
A
A
Paolucci
E
E
Rotilio
G
G
Carrì
M T
MT
D000818:Animals; D001205:Ascorbic Acid / Q000494:pharmacology; D019703:Calcineurin / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism; D004229:Dithiothreitol / Q000494:pharmacology; D006624:Hippocampus / Q000378:metabolism; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009044:Motor Cortex / Q000378:metabolism; D016472:Motor Neuron Disease / Q000201:enzymology* / Q000235:genetics; D009447:Neuroblastoma; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D011994:Recombinant Proteins / Q000378:metabolism; D013116:Spinal Cord / Q000378:metabolism; D013482:Superoxide Dismutase / Q000235:genetics* / Q000378:metabolism*; D014162:Transfection; D014407:Tumor Cells, Cultured
D011994:Recombinant Proteins; D013482:Superoxide Dismutase; D019703:Calcineurin; D001205:Ascorbic Acid; D002118:Calcium; D004229:Dithiothreitol