HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

J. Biol. Chem., Vol. 283, Issue 37, 25628-25637, September 12, 2008

This Article Full Text Full Text (PDF) All Versions of this Article: 283/37/25628    most recent M804291200v1 Submit a Letter to Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Quintanilla, R. A. Articles by Johnson, G. V. W. Search for Related Content PubMed PubMed Citation Articles by Quintanilla, R. A. Articles by Johnson, G. V. W. Social Bookmarking                      What's this?

Rosiglitazone Treatment Prevents Mitochondrial Dysfunction in Mutant Huntingtin-expressing Cells

POSSIBLE ROLE OF PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR- (PPAR) IN THE PATHOGENESIS OF HUNTINGTON DISEASE^*

Rodrigo A. Quintanilla, Youngnam N. Jin, Karen Fuenzalida^¶, Miguel Bronfman^¶, and Gail V. W. Johnson¹

From the Department of Anesthesiology, University of Rochester, Rochester, New York 14642, the Department of Pharmacology and Physiology, University of Rochester, Rochester, New York 14642-0002, and the ^¶Centro de Regulación Celular y Patologia Joaquín V. Luco and Millennium Institute for Fundamental and Applied Biology, Department of Cellular and Molecular Biology, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Alameda 340, Santiago 114-D, Chile

Peroxisome proliferator-activated receptor- (PPAR) is a member of the PPAR family of transcription factors. Synthetic PPAR agonists are used as oral anti-hyperglycemic drugs for the treatment of non-insulin-dependent diabetes. However, emerging evidence indicates that PPAR activators can also prevent or attenuate neurodegeneration. Given these previous findings, the focus of this report is on the potential neuroprotective role of PPAR activation in preventing the loss of mitochondrial function in Huntington disease (HD). For these studies we used striatal cells that express wild-type (STHdh^Q7/Q7) or mutant (STHdh^Q111/Q111) huntingtin protein at physiological levels. Treatment of mutant cells with thapsigargin resulted in a significant decrease in mitochondrial calcium uptake, an increase in reactive oxygen species production, and a significant decrease in mitochondrial membrane potential. PPAR activation by rosiglitazone prevented the mitochondrial dysfunction and oxidative stress that occurred when mutant striatal cells were challenged with pathological increases in calcium. The beneficial effects of rosiglitazone were likely mediated by activation of PPAR, as all protective effects were prevented by the PPAR antagonist GW9662. Additionally, the PPAR signaling pathway was significantly impaired in the mutant striatal cells with decreases in PPAR expression and reduced PPAR transcriptional activity. Treatment with rosiglitazone increased mitochondrial mass levels, suggesting a role for the PPAR pathway in mitochondrial function in striatal cells. Altogether, this evidence indicates that PPAR activation by rosiglitazone attenuates mitochondrial dysfunction in mutant huntingtin-expressing striatal cells, and this could be an important therapeutic avenue to ameliorate the mitochondrial dysfunction that occurs in HD.

Received for publication, June 4, 2008 , and in revised form, July 15, 2008.

^* This work was supported, in whole or in part, by National Institutes of Health Grant NS041744. 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.

¹ To whom correspondence should be addressed: Dept. of Anesthesiology University of Rochester Medical Center, 601 Elmwood Ave. Box 604 (for courier: Rm 4-6314), Rochester, NY 14642. Tel.: 585-276-3740; Fax: 585-276-2418; E-mail: gail_johnsonvoll{at}urmc.rochester.edu.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				R. A. Quintanilla, T. A. Matthews-Roberson, P. J. Dolan, and G. V. W. Johnson Caspase-cleaved Tau Expression Induces Mitochondrial Dysfunction in Immortalized Cortical Neurons: IMPLICATIONS FOR THE PATHOGENESIS OF ALZHEIMER DISEASE J. Biol. Chem., July 10, 2009; 284(28): 18754 - 18766. [Abstract] [Full Text] [PDF]

				J. Phan, M. A. Hickey, P. Zhang, M.-F. Chesselet, and K. Reue Adipose tissue dysfunction tracks disease progression in two Huntington's disease mouse models Hum. Mol. Genet., March 15, 2009; 18(6): 1006 - 1016. [Abstract] [Full Text] [PDF]