Heterotrimeric protein phosphatase 2A (PP2A) is a major Ser/Thr phosphatase that regulates many cellular signal transduction pathways. The neuron-specific B-beta regulatory subunit of PP2A appears to be a critical survival regulator, since a CAG repeat expansion in its promoter is responsible for the neurodegenerative disorder spinocerebellar ataxia type-12. Recently published work from our laboratory has demonstrated that B-beta2, a splice variant of B-beta, contains a N-terminal targeting sequences that directs PP2A to mitochondria to promote apoptosis in a neuronal cell line. Here, I propose to investigate the mechanism by which B-beta2 binds to mitochondria and antagonizes survival. In three aims, I will address the hypotheses that B-beta2 promotes apoptosis by (1) blocking the mitochondrial import receptor, (2) dephosphorylating Bcl-2 family survival regulators at the outer mitochondrial membrane, and by (3) interfering with mitochondrial metabolism. The findings in this proposal will be relevant for the development of novel therapies that target B-beta2 to prevent apoptosis during brain ischemia and neurodegeneration. ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Predoctoral Individual National Research Service Award (F31)
Project #
1F31NS049659-01
Application #
6831123
Study Section
Special Emphasis Panel (ZRG1-CDF-1 (29))
Program Officer
Nunn, Michael
Project Start
2004-08-01
Project End
2007-07-31
Budget Start
2004-08-01
Budget End
2005-07-31
Support Year
1
Fiscal Year
2004
Total Cost
$27,513
Indirect Cost
Name
University of Iowa
Department
Pharmacology
Type
Schools of Medicine
DUNS #
062761671
City
Iowa City
State
IA
Country
United States
Zip Code
52242
Merrill, Ronald A; Dagda, Ruben K; Dickey, Audrey S et al. (2011) Mechanism of neuroprotective mitochondrial remodeling by PKA/AKAP1. PLoS Biol 9:e1000612