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 cellu lar responses to calcium-mobilizing signals, and a role for this enzyme in neuropathology has been postulated. We have investigated the possibility th at redox modulation of CN activity is relevant to neuropathological conditi ons where an imbalance in reactive oxygen species has been described. We ha ve 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 existe nce of a redox regulation of this enzyme has been also obtained by overexpr ession of wild-type antioxidant Cu,Zn superoxide dismutase (SOD1) that prom otes CN activity and protects it from oxidative inactivation. On the contra ry, overexpression of mutant SOD1s associated with familial amyotrophic lat eral sclerosis (FALS) impairs CN activity both in transfected human neurobl astoma cell lines and in the motor cortex of brain from FALS-transgenic mic e. These data suggest that CN might be a target in the pathogenesis of SOD1 -linked FALS.