Bcl2-A1 interacts with pro-caspase-3: implications for amyotrophic lateral sclerosis

Ciro Iaccarino; Maria Elena Mura; Sonia Esposito; Franco Carta; Giovanna Sanna; Franco Turrini; Maria Teresa Carrì; Claudia Crosio

doi:10.1016/j.nbd.2011.05.013

Bcl2-A1 interacts with pro-caspase-3: implications for amyotrophic lateral sclerosis

Neurobiol Dis. 2011 Sep;43(3):642-50. doi: 10.1016/j.nbd.2011.05.013. Epub 2011 May 25.

Authors

Ciro Iaccarino¹, Maria Elena Mura, Sonia Esposito, Franco Carta, Giovanna Sanna, Franco Turrini, Maria Teresa Carrì, Claudia Crosio

Affiliation

¹ Dept of Physiological, Biochemical and Cell Science, University of Sassari, Via Muroni 25, 07100 Sassari, Italy. ciaccarino@uniss.it

PMID: 21624464
DOI: 10.1016/j.nbd.2011.05.013

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Amyotrophic Lateral Sclerosis / enzymology
Amyotrophic Lateral Sclerosis / genetics*
Amyotrophic Lateral Sclerosis / metabolism*
Animals
Apoptosis / genetics*
Caspase 3 / genetics*
Caspase 3 / metabolism
Caspase Inhibitors
Cell Line, Transformed
Cell Survival / genetics
Enzyme Precursors / genetics
Enzyme Precursors / metabolism
HEK293 Cells
Humans
Mice
Mice, Inbred C57BL
Mice, Transgenic
Minor Histocompatibility Antigens
Motor Neurons / enzymology
Motor Neurons / metabolism
Motor Neurons / pathology
Oxidation-Reduction
Protein Structure, Tertiary / genetics
Proto-Oncogene Proteins c-bcl-2 / biosynthesis
Proto-Oncogene Proteins c-bcl-2 / genetics*
Proto-Oncogene Proteins c-bcl-2 / metabolism
Superoxide Dismutase / genetics*
Superoxide Dismutase / metabolism
Superoxide Dismutase-1
Transcription Factor AP-1 / genetics
Transcription Factor AP-1 / metabolism
Up-Regulation / genetics

Substances

BCL2-related protein A1
Caspase Inhibitors
Enzyme Precursors
Minor Histocompatibility Antigens
Proto-Oncogene Proteins c-bcl-2
SOD1 protein, human
Transcription Factor AP-1
Sod1 protein, mouse
Superoxide Dismutase
Superoxide Dismutase-1
Casp3 protein, mouse
Caspase 3