Journal article
Mutant huntingtin binds the mitochondrial fission GTPase dynamin-related protein-1 and increases its enzymatic activity
W Song, J Chen, A Petrilli, G Liot, E Klinglmayr, Y Zhou, P Poquiz, J Tjong, MA Pouladi, MR Hayden, E Masliah, M Ellisman, I Rouiller, R Schwarzenbacher, B Bossy, G Perkins, E Bossy-Wetzel
Nature Medicine | NATURE PUBLISHING GROUP | Published : 2011
DOI: 10.1038/nm.2313
Abstract
Huntington's disease is an inherited and incurable neurodegenerative disorder caused by an abnormal polyglutamine (polyQ) expansion in huntingtin (encoded by HTT). PolyQ length determines disease onset and severity, with a longer expansion causing earlier onset. The mechanisms of mutant huntingtin-mediated neurotoxicity remain unclear; however, mitochondrial dysfunction is a key event in Huntington's disease pathogenesis. Here we tested whether mutant huntingtin impairs the mitochondrial fission-fusion balance and thereby causes neuronal injury. We show that mutant huntingtin triggers mitochondrial fragmentation in rat neurons and fibroblasts of individuals with Huntington's disease in vitro..
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Awarded by National Eye Institute
Funding Acknowledgements
We thank S. Finkbeiner (University of California-San Francisco) for the pGW1 plasmids encoding huntingtin<SUP>ex1</SUP>-Q<INF>17</INF>-GFP, huntingtine<SUP>x1-</SUP>Q<INF>46</INF>-GFP, huntingtin<SUP>ex1</SUP>-Q<INF>97-</INF>GFP; L. Thompson (University of California-Irvine) for the huntingtin plasmids pcDNA3.1-Q25-GFP and pcDNA3.1-Q97-GFP; U. Hartl (Max Planck Institute of Biochemistry) for the GST-huntingtin<SUP>ex1</SUP>-Q<INF>20</INF> and -Q<INF>53</INF> constructs; A. van der Bliek (University of California-Los Angeles) for the DRP1 K38A cDNA in baculovirus expression vector (US National Center for Biotechnology Information accession number NM_005690.3); R. Youle (US National Institutes of Health (NIH)) for the YFP-DRP1 plasmid; R. Slack (University of Ottawa) for the MFN2 RasG12V (p82-FzoRV12pECFP-C1) expression plasmid; S. Strack (University of Iowa) for his pcDNA3.1 beta-DRP1shRNA vector; S. Lubitz, J. Johnson, V. DeAssis, C. Eldon and B. Kincaid for technical assistance; and A. Knott for manuscript development and editing. This work is supported by NIH grants to E.B.-W. (R01EY016164 and R01NS055193), a fellowship from the Hereditary Disease Foundation (to G. L.), grants to I. R., M. A. P. and M. R. H. from the Canadian Institutes of Health Research, and support from CHDI to M. R. H. The electron microscope tomography work was carried out in facilities of the US National Center for Microscopy and Imaging Research, supported by NIH grant P41RR004050 awarded to M. E.