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

Content Provider	PubMed Central
Author	Lee, Jean-pyo Palfrey, H. Clive Bindokas, Vytautas P. Ghadge, Ghanashyam D. Ma, Li Miller, Richard J. Roos, Raymond P.
Copyright Year	1999
Abstract	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.
Starting Page	3251
File Format	PDF
ISSN	10916490
e-ISSN	10916490
Journal	Proceedings of the National Academy of Sciences of the United States of America
Issue Number	6
Volume Number	96
Language	English
Publisher	The National Academy of Sciences
Publisher Date	1999-03-16
Access Restriction	Open
Rights Holder	The National Academy of Sciences
Subject Keyword	Research in Higher Education
Content Type	Text
Resource Type	Article
Subject	Multidisciplinary

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

Formation of high molecular weight complexes of mutant Cu,Zn-superoxide dismutase in a mouse model for familial amyotrophic lateral sclerosis

Loss of in Vitro Metal Ion Binding Specificity in Mutant Copper-Zinc Superoxide Dismutases Associated with Familial Amyotrophic Lateral Sclerosis

Absence of neurofilaments reduces the selective vulnerability of motor neurons and slows disease caused by a familial amyotrophic lateral sclerosis-linked superoxide dismutase 1 mutant

Superoxide dismutase 1 with mutations linked to familial amyotrophic lateral sclerosis possesses significant activity.

Common dynamical signatures of familial amyotrophic lateral sclerosis-associated structurally diverse Cu, Zn superoxide dismutase mutants

Therapeutic effects of immunization with mutant superoxide dismutase in mice models of amyotrophic lateral sclerosis

Common dynamical signatures of familial amyotrophic lateral sclerosis-associated structurally diverse Cu, Zn superoxide dismutase mutants.

Strategies for stabilizing superoxide dismutase (SOD1), the protein destabilized in the most common form of familial amyotrophic lateral sclerosis

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

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

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