Journal Article

Increased energy metabolism rescues glia-induced pathology in a <i>Drosophila</i> model of Huntington's disease

Marie-Thérèse Besson, Pascale Dupont, Yih-Woei C. Fridell and Jean-Charles Liévens

in Human Molecular Genetics

Volume 19, issue 17, pages 3372-3382
Published in print September 2010 | ISSN: 0964-6906
Published online June 2010 | e-ISSN: 1460-2083 | DOI: http://dx.doi.org/10.1093/hmg/ddq249
Increased energy metabolism rescues glia-induced pathology in a Drosophila model of Huntington's disease

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Huntington's disease (HD) is a polyglutamine (polyQ) disease caused by an expanded CAG tract within the coding region of Huntingtin protein. Mutant Huntingtin (mHtt) is ubiquitously expressed, abundantly in neurons but also significantly in glial cells. Neuron-intrinsic mechanism and alterations in glia-to-neuron communication both contribute to the neuronal dysfunction and death in HD pathology. However, it remains to be determined the role of glial cells in HD pathogenesis. In recent years, development of Drosophila models facilitated the dissection of the cellular and molecular events in polyQ-related diseases. By using genetic approaches in Drosophila, we manipulated the expression levels of mitochondrial uncoupling proteins (UCPs) that regulate production of both ATP and reactive oxygen species in mitochondria. We discovered that enhanced levels of UCPs alleviated the HD phenotype when mHtt was selectively expressed in glia, including defects in locomotor behavior and early death of Drosophila. In contrast, UCPs failed to prevent the HD toxicity in neurons. Increased oxidative stress defense was found to rescue neuron but not glia-induced pathology. Evidence is now emerging that UCPs are fundamental to adapt the energy metabolism in order to meet the metabolic demand. Thus, we propose that UCPs are glioprotective by rescuing energy-dependent functions in glia that are challenged by mHtt. In support of this, increasing glucose entry in glia was found to alleviate glia-induced pathology. Altogether, our data emphasize the importance of energy metabolism in the glial alterations in HD and may lead to a new therapeutic avenue.

Journal Article.  6137 words.  Illustrated.

Subjects: Genetics and Genomics

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