Format

Send to

Choose Destination
See comment in PubMed Commons below
J Cereb Blood Flow Metab. 2013 Feb;33(2):196-204. doi: 10.1038/jcbfm.2012.150. Epub 2012 Oct 17.

PHLPP1 gene deletion protects the brain from ischemic injury.

Author information

1
Department of Neurology, Cedars-Sinai Medical Center, Los Angeles, California, USA.

Abstract

A recently discovered protein phosphatase PHLPP (PH domain Leucine-rich repeat Protein Phosphatase) has been shown to dephosphorylate Akt on its hydrophobic motif (Ser473) thereby decreasing Akt kinase activity. We generated PHLPP1 knockout (KO) mice and used them to explore the ability of enhanced in vivo Akt signaling to protect the brain against ischemic insult. Brains from KO mice subjected to middle cerebral artery occlusion (MCAO) for 2 hours showed significantly greater increases in Akt activity and less neurovascular damage after reperfusion than wild-type (WT) mice. Remarkably, infarct volume in the PHLPP1 KO was significantly reduced compared with WT (12.7±2.7% versus 22.9±3.1%) and this was prevented by Akt inhibition. Astrocytes from KO mice and neurons in which PHLPP1 was downregulated showed enhanced Akt activation and diminished cell death in response to oxygen-glucose deprivation. Thus, deletion of PHLPP1 can enhance Akt activation in neurons and astrocytes, and can significantly increase cell survival and diminish infarct size after MCAO. Inhibition of PHLPP could be a therapeutic approach to minimize damage after focal ischemia.

PMID:
23072745
PMCID:
PMC3564187
DOI:
10.1038/jcbfm.2012.150
[Indexed for MEDLINE]
Free PMC Article

Publication types, MeSH terms, Substances, Grant support

PubMed Commons home

PubMed Commons

0 comments
How to join PubMed Commons

    Supplemental Content

    Full text links

    Icon for Atypon Icon for PubMed Central
    Loading ...
    Support Center