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

It has been reported that expression of familial amyotrophic lateral sclerosis (FALS)-associated mutant Cu/Zn superoxide dismutase-1 (SOD) induces apoptosis of neuronal cells in culture associated with an increase in reactive oxygen species. SOD recently has been shown to prevent calcineurin inactiv...

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Published in:Proceedings of the National Academy of Sciences - PNAS 1999-03, Vol.96 (6), p.3251-3256
Main Authors: Lee, J P, Palfrey, H C, Bindokas, V P, Ghadge, G D, Ma, L, Miller, R J, Roos, R P
Format: Article
Language:English
Subjects:
Adenoviridae
Amyotrophic Lateral Sclerosis - genetics
Amyotrophic Lateral Sclerosis - pathology
Animals
Apoptosis - genetics
Biological Sciences
Calcineurin - genetics
Gene Expression Regulation
Genetic Vectors
Humans
Immunophilins - genetics
Mutation
Neurons - pathology
PC12 Cells
Rats
Superoxide Dismutase - genetics
Transfection
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Summary:It has been reported that expression of familial amyotrophic lateral sclerosis (FALS)-associated mutant Cu/Zn superoxide dismutase-1 (SOD) induces apoptosis of neuronal cells in culture associated with an increase in reactive oxygen species. SOD recently has been shown to prevent calcineurin inactivation, initiating the present investigations examining the role of calcineurin in mutant SOD-induced cell death. Wild-type or mutant SOD was expressed in neuronal cells by infection with replication-deficient adenoviruses. PC12 cells overexpressing human wild-type SOD exhibited higher calcineurin activity than cells expressing FALS-related mutant SOD (SODV148G); however, cells expressing SODV148G had calcineurin activity equal to mock-infected cells, suggesting that cell death induced by mutant SOD was not related to a decrease in calcineurin activity. Calcineurin antagonists such as cyclosporin A and FK506, as well as nonimmunosuppressant analogs of cyclosporin A, significantly enhanced SODV148G- and SODA4V-induced cell death. Because both 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 SODV148G expression. The importance of rotamase activity in mutant SOD-mediated apoptosis was supported by experiments showing that overexpressed wild-type cyclophilin A (CyPA), but not CyPA with a rotamase active site point mutation, protected cells from death after SODV148G expression. These data suggest that mutant SOD produces a greater need for rotamase and, also, highlights possible new therapeutic strategies in FALS.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.96.6.3251