The role of immunophilins in mutant superoxide dismutase-1-linked familialamyotrophic lateral sclerosis

It has been reported that expression of familial amyotrophic lateral sclero sis (FALS)-associated mutant Cu/Zn superoxide dismutase-l (SOD) induces apo ptosis of neuronal cells in culture associated with an increase in reactive oxygen species. SOD recently has been shown to prevent calcineurin inactiv ation, initiating the present investigations examining the role of calcineu rin in mutant SOD-induced cell death. Wild-type or mutant SOD was expressed in neuronal cells by infection with replication-deficient adenoviruses, PC 12 cells overexpressing human wild-type SOD exhibited higher calcineurin ac tivity than cells expressing FALS-related mutant SOD (SODV148G); however, c ells ex pressing SODV148G had calcineurin activity equal to mock-infected c ells, suggesting that cell death induced by mutant SOD was not related to a decrease in calcineurin activity, Calcineurin antagonists such as cyclospo rin A and FK506, as well as nonimmunosuppressant analogs of cyclosporin A, significantly enhanced SODV148G- and SODA4V-induced cell death. Because bot h groups of drugs inhibit the rotamase activity of cyclophilins (CyP), but only the immunosuppressant analogs inhibit calcineurin activity, these data suggest that rotamase inhibition underlies the enhanced cell death after S ODV148G expression, The importance of rotamase activity in mutant SOD-media ted apoptosis was supported by experiments showing that overexpressed wild- type cyclophilin A (CyPA), but not CyPA with a rotamase active site point m utation, protected cells from death after SODV148G expression. These data s uggest that mutant SOD produces a greater need for rotamase and, also, high lights possible new therapeutic strategies in FALS.