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Originally published In Press as doi:10.1074/jbc.M309348200 on October 1, 2003

J. Biol. Chem., Vol. 278, Issue 50, 50514-50522, December 12, 2003
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Enhanced Akt Signaling Is an Early Pro-survival Response That Reflects N-Methyl-D-aspartate Receptor Activation in Huntington's Disease Knock-in Striatal Cells*

Silvia Gines{ddagger}§, Elena Ivanova{ddagger}, Ihn-Sik Seong{ddagger}, Carlos A. Saura¶, and Marcy E. MacDonald{ddagger}

From the {ddagger}Molecular Neurogenetics Unit, Massachusetts General Hospital, Charlestown Massachusetts 02129 and the Center for Neurologic Diseases, Brigham and Women's Hospital, Boston, Massachusetts 02115

Huntington's disease features the loss of striatal neurons that stems from a disease process that is initiated by mutant huntingtin. Early events in the disease cascade, which predate overt pathology in Hdh CAG knock-in mouse striatum, implicate enhanced N-methyl-D-aspartate (NMDA) receptor activation, with excitotoxity caused by aberrant Ca2+ influx. Here we demonstrate in precise genetic Huntington's disease mouse and striatal cell models that these early phenotypes are associated with activation of the Akt pro-survival signaling pathway. Elevated levels of activated Ser(P)473-Akt are detected in extracts of HdhQ111/Q111 striatum and cultured mutant STHdhQ111/Q111 striatal cells, compared with their wild type counterparts. Akt activation in mutant striatal cells is associated with increased Akt signaling via phosphorylation of GSK3{beta} at Ser9. Consequent decreased turnover of transcription co-factor {beta}-catenin leads to increased levels of {beta}-catenin target gene cyclin D1. Akt activation is phosphatidylinositol 3-kinase dependent, as demonstrated by increased levels of Ser(P)241-PDK1 kinase and decreased Ser(P)380-PTEN phosphatase. Moreover, Akt activation can be normally stimulated by treatment with insulin growth factor-1 and blocked by treatment with the phosphatidylinositol 3-kinase inhibitor LY294002. However, in contrast to wild type cells, Akt activation in mutant striatal cells can be blocked by the addition of the NMDA receptor antagonist MK-801. Akt activation in mutant striatal cells is Ca2+-dependent, because treatment with EGTA reduces levels of Ser(P)473-Akt. Thus, consistent with excitotoxicity early in the disease process, activation of the Akt pro-survival pathway in mutant knock-in striatal cells predates overt pathology and reflects mitochondrial dysfunction and enhanced NMDA receptor signaling.

Received for publication, August 22, 2003 , and in revised form, September 22, 2003.

* This work was supported by NINDS, National Institutes of Health Grants NS32765 and NS16367 (Huntington's Disease Center Without Walls), an anonymous donor, and the Huntington's Disease Society of America (Coalition for the Cure). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

§ To whom correspondence should be addressed: Molecular Neurogenetics Unit, Massachusetts General Hospital, Bldg. 149, 13th St., Charlestown, MA 02129. Tel.: 617-726-5726; Fax: 617-726-5735; E-mail: gines{at}helix.mgh.harvard.edu.


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