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The Journal of Neuroscience, March 12, 2008, 28(11):2783-2792; doi:10.1523/JNEUROSCI.0106-08.2008

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Neurobiology of Disease
N-Terminal Mutant Huntingtin Associates with Mitochondria and Impairs Mitochondrial Trafficking

Adam L. Orr,¹ Shihua Li,¹ Chuan-En Wang,¹ He Li,^1,2 Jianjun Wang,¹ Juan Rong,¹ Xingshun Xu,¹ Pier Giorgio Mastroberardino,³ J. Timothy Greenamyre,³ and Xiao-Jiang Li¹

¹Department of Human Genetics, Emory University School of Medicine, Atlanta, Georgia 30322, ²Division of Histology and Embryology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, People's Republic of China, and ³Pittsburgh Institute for Neurodegenerative Diseases and the Department of Neurology, University of Pittsburgh, Pittsburgh, Pennsylvania 15260

Correspondence should be addressed to Dr. Xiao-Jiang Li, Department of Human Genetics, Emory University School of Medicine, Atlanta, GA 30322. Email: xiaoli{at}genetics.emory.edu

Huntington's disease (HD) is caused by polyglutamine (polyQ) expansion in huntingtin (htt), a large (350 kDa) protein that localizes predominantly to the cytoplasm. Proteolytic cleavage of mutant htt yields polyQ-containing N-terminal fragments that are prone to misfolding and aggregation. Disease progression in HD transgenic models correlates with age-related accumulation of soluble and aggregated forms of N-terminal mutant htt fragments, suggesting that multiple forms of mutant htt are involved in the selective neurodegeneration in HD. Although mitochondrial dysfunction is implicated in the pathogenesis of HD, it remains unclear which forms of cytoplasmic mutant htt associate with mitochondria to affect their function. Here we demonstrate that specific N-terminal mutant htt fragments associate with mitochondria in Hdh(CAG)150 knock-in mouse brain and that this association increases with age. The interaction between soluble N-terminal mutant htt and mitochondria interferes with the in vitro association of microtubule-based transport proteins with mitochondria. Mutant htt reduces the distribution and transport rate of mitochondria in the processes of cultured neuronal cells. Reduced ATP level was also found in the synaptosomal fraction isolated from Hdh(CAG)150 knock-in mouse brain. These findings suggest that specific N-terminal mutant htt fragments, before the formation of aggregates, can impair mitochondrial function directly and that this interaction may be a novel target for therapeutic strategies in HD.

Key words: polyglutamine; mitochondria; trafficking; neurodegeneration; Huntington's disease; proteolysis

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Received Aug. 15, 2007; revised Feb. 4, 2008; accepted Feb. 4, 2008.

Correspondence should be addressed to Dr. Xiao-Jiang Li, Department of Human Genetics, Emory University School of Medicine, Atlanta, GA 30322. Email: xiaoli{at}genetics.emory.edu

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