Abstract
Expression of mutant SOD1 typical of familial amyotrophic lateral sclerosis (ALS) induces the expression of Bcl2-A1, a member of the Bcl2 family of proteins, specifically in motor neurons of transgenic mice. In this work, we have used immortalized motor neurons (NSC-34) and transgenic mice expressing mutant SOD1 to unravel the molecular mechanisms and the biological meaning of this up-regulation. We report that up-regulation of Bcl2-A1 by mutant SOD1 is mediated by activation of the redox sensitive transcription factor AP1 and that Bcl2-A1 interacts with pro-caspase-3 via its C-terminal helix α9. Furthermore, Bcl2-A1 inhibits pro-caspase-3 activation in immortalized motor neurons expressing mutant SOD1 and thus induction of Bcl2-A1 in ALS mice represents a pro-survival strategy aimed at counteracting the toxic effects of mutant SOD1. These data provide significant new insights on how molecular signaling, driven by expression of the ALS-causative gene SOD1, affects regulation of apoptosis in motor neurons and thus may have implications for ALS therapy, where prevention of motor neuronal cell death is one of the major aims.
Copyright © 2011 Elsevier Inc. All rights reserved.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Amyotrophic Lateral Sclerosis / enzymology
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Amyotrophic Lateral Sclerosis / genetics*
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Amyotrophic Lateral Sclerosis / metabolism*
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Animals
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Apoptosis / genetics*
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Caspase 3 / genetics*
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Caspase 3 / metabolism
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Caspase Inhibitors
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Cell Line, Transformed
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Cell Survival / genetics
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Enzyme Precursors / genetics
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Enzyme Precursors / metabolism
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HEK293 Cells
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Humans
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Mice
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Mice, Inbred C57BL
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Mice, Transgenic
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Minor Histocompatibility Antigens
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Motor Neurons / enzymology
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Motor Neurons / metabolism
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Motor Neurons / pathology
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Oxidation-Reduction
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Protein Structure, Tertiary / genetics
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Proto-Oncogene Proteins c-bcl-2 / biosynthesis
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Proto-Oncogene Proteins c-bcl-2 / genetics*
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Proto-Oncogene Proteins c-bcl-2 / metabolism
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Superoxide Dismutase / genetics*
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Superoxide Dismutase / metabolism
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Superoxide Dismutase-1
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Transcription Factor AP-1 / genetics
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Transcription Factor AP-1 / metabolism
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Up-Regulation / genetics
Substances
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BCL2-related protein A1
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Caspase Inhibitors
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Enzyme Precursors
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Minor Histocompatibility Antigens
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Proto-Oncogene Proteins c-bcl-2
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SOD1 protein, human
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Transcription Factor AP-1
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Sod1 protein, mouse
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Superoxide Dismutase
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Superoxide Dismutase-1
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Casp3 protein, mouse
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Caspase 3