The spinocerebellar ataxia 12 gene product and protein phosphatase 2A regulatory subunit Bβ2 antagonizes neuronal survival by promoting mitochondrial fission

Ruben K. Dagda, Ronald A. Merrill, J. Thomas Cribbs, Yucui Chen, Johannes W Hell, Yuriy M. Usachev, Stefan Strack

Research output: Contribution to journalArticle

63 Scopus citations

Abstract

The neurodegenerative disorder spinocerebellar ataxia 12 (SCA12) is caused by CAG repeat expansion in the non-coding region of the PPP2R2B gene. PPP2R2B encodes Bβ1 and Bβ2, alternatively spliced and neuron-specific regulatory subunits of the protein phosphatase 2A (PP2A) holoenzyme. We show here that in PC12 cells and hippocampal neurons, cell stressors induced a rapid translocation of PP2A/Bβ2 to mitochondria to promote apoptosis. Conversely, silencing of PP2A/Bβ2 protected hippocampal neurons against free radical-mediated, excitotoxic, and ischemic insults. Evidence is accumulating that the mitochondrial fission/fusion equilibrium is an important determinant of cell survival. Accordingly, we found that Bβ2 expression induces mitochondrial fragmentation, whereas Bβ2 silencing or inhibition resulted in mitochondrial elongation. Based on epistasis experiments involving Bcl2 and core components of the mitochondrial fission machinery (Fis1 and dynamin-related protein 1), mitochondrial fragmentation occurs upstream of apoptosis and is both necessary and sufficient for hippocampal neuron death. Our data provide the first example of a proapoptotic phosphatase that predisposes to neuronal death by promoting mitochondrial division and point to a possible imbalance of the mitochondrial morphogenetic equilibrium in the pathogenesis of SCA12.

Original languageEnglish (US)
Pages (from-to)36241-36248
Number of pages8
JournalJournal of Biological Chemistry
Volume283
Issue number52
DOIs
StatePublished - Dec 26 2008
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

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