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Human Molecular Genetics Advance Access originally published online on August 22, 2005
Human Molecular Genetics 2005 14(19):2871-2880; doi:10.1093/hmg/ddi319
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© The Author 2005. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

HD CAG repeat implicates a dominant property of huntingtin in mitochondrial energy metabolism

Ihn Sik Seong1, Elena Ivanova1, Jong-Min Lee1, Yeun Su Choo2, Elisa Fossale1, MaryAnne Anderson1, James F. Gusella1, Jason M. Laramie3, Richard H. Myers3, Mathieu Lesort2 and Marcy E. MacDonald1,*

1Molecular Neurogenetics Unit, Center for Human Genetic Research, Massachusetts General Hospital, Richard B. Simches Research Center, 185 Cambridge Street, Boston, MA 02114, USA, 2Department of Psychiatry, University of Alabama at Birmingham, Birmingham, AL 35294, USA and 3Department of Neurology, Boston University School of Medicine, 715 Albany Street, Boston, MA 02118, USA

* To whom correspondence should be addressed. Tel: +1 6177265089; Fax: +1 6177265735; Email: macdonam{at}helix.mgh.harvard.edu

Received July 23, 2005; Revised August 10, 2005; Accepted August 16, 2005

The ‘expanded’ HD CAG repeat that causes Huntington's disease (HD) encodes a polyglutamine tract in huntingtin, which first targets the death of medium-sized spiny striatal neurons. Mitochondrial energetics, related to N-methyl-D-aspartate (NMDA) Ca2+-signaling, has long been implicated in this neuronal specificity, implying an integral role for huntingtin in mitochondrial energy metabolism. As a genetic test of this hypothesis, we have looked for a relationship between the length of the HD CAG repeat, expressed in endogenous huntingtin, and mitochondrial ATP production. In STHdhQ111 knock-in striatal cells, a juvenile onset HD CAG repeat was associated with low mitochondrial ATP and decreased mitochondrial ADP-uptake. This metabolic inhibition was associated with enhanced Ca2+-influx through NMDA receptors, which when blocked resulted in increased cellular [ATP/ADP]. We then evaluated [ATP/ADP] in 40 human lymphoblastoid cell lines, bearing non-HD CAG lengths (9–34 units) or HD-causing alleles (35–70 units). This analysis revealed an inverse association with the longer of the two allelic HD CAG repeats in both the non-HD and HD ranges. Thus, the polyglutamine tract in huntingtin appears to regulate mitochondrial ADP-phosphorylation in a Ca2+-dependent process that fulfills the genetic criteria for the HD trigger of pathogenesis, and it thereby determines a fundamental biological parameter—cellular energy status, which may contribute to the exquisite vulnerability of striatal neurons in HD. Moreover, the evidence that this polymorphism can determine energy status in the non-HD range suggests that it should be tested as a potential physiological modifier in both health and disease.


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