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The Journal of Neuroscience, May 31, 2006, 26(22):6019-6030; doi:10.1523/JNEUROSCI.1251-06.2006

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Neurobiology of Disease
Regulation of Intracellular Trafficking of Huntingtin-Associated Protein-1 Is Critical for TrkA Protein Levels and Neurite Outgrowth

Juan Rong, John R. McGuire, Zhi-Hui Fang, Guoqing Sheng, Ji-Yeon Shin, Shi-Hua Li, and Xiao-Jiang Li

Department of Human Genetics, Emory University School of Medicine, Atlanta, Georgia 30322

Correspondence should be addressed to Dr. Xiao-Jiang Li, Department of Human Genetics, Emory University School of Medicine, 615 Michael Street, Atlanta, GA 30322. Email: xiaoli{at}genetics.emory.edu

Mutant huntingtin can affect vesicular and receptor trafficking via its abnormal protein interactions, suggesting that impairment of intracellular trafficking may contribute to Huntington's disease. There is growing evidence that huntingtin-associated protein-1 (HAP1) also interacts with microtubule-dependent transporters and is involved in intracellular trafficking. However, it remains unclear how the trafficking of HAP1 is regulated and contributes to neuronal function. Here we report that phosphorylation of HAP1 decreases its association with microtubule-dependent transport proteins dynactin p150 and kinesin light chain and reduces its localization in neurite tips. Suppressing HAP1 expression by RNA interference reduces neurite outgrowth and the level of tropomyosin-related kinase A receptor tyrosine kinase (TrkA), a nerve growth factor receptor whose internalization and trafficking are required for neurite outgrowth. HAP1 maintains the normal level of membrane TrkA by preventing the degradation of internalized TrkA. Mutant huntingtin also reduces the association of HAP1 with dynactin p150 and kinesin light chain and thereby decreases the intracellular level of TrkA. These findings suggest that HAP1 trafficking is critical for the stability of TrkA and neurite function, both of which can be attenuated by mutant huntingtin.

Key words: huntingtin; neuropathology; TrkA; polyglutamine; neurite; trafficking

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Received Jan. 8, 2006; revised April 24, 2006; accepted April 25, 2006.

Correspondence should be addressed to Dr. Xiao-Jiang Li, Department of Human Genetics, Emory University School of Medicine, 615 Michael Street, Atlanta, GA 30322. Email: xiaoli{at}genetics.emory.edu

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