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The Journal of Neuroscience, January 7, 2004, 24(1):269-281; doi:10.1523/JNEUROSCI.1409-03.2004

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Neurobiology of Disease
Huntingtin Bodies Sequester Vesicle-Associated Proteins by a Polyproline-Dependent Interaction

Zheng-Hong Qin,¹ Yumei Wang,¹ Ellen Sapp,¹ Benjamin Cuiffo,¹ Erich Wanker,³ Michael R. Hayden,⁴ Kimberly B. Kegel,¹ Neil Aronin,² and Marian DiFiglia¹

¹Laboratory of Cellular Neurobiology, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts 02129, ²Departments of Medicine and Cell Biology, University of Massachusetts Medical Center, Worcester, Massachusetts 01655, ³Max-Planck-Institut for Molecular Genetics, D-14195 Berlin, Germany, and ⁴Molecular Medicine and Therapeutics, University of British Columbia, Vancouver, British Columbia V5Z 4H4, Canada

Polyglutamine expansion in the N terminus of huntingtin (htt) causes selective neuronal dysfunction and cell death by unknown mechanisms. Truncated htt expressed in vitro produced htt immunoreactive cytoplasmic bodies (htt bodies). The fibrillar core of the mutant htt body resisted protease treatment and contained cathepsin D, ubiquitin, and heat shock protein (HSP) 40. The shell of the htt body was composed of globules 14-34 nm in diameter and was protease sensitive. HSP70, proteasome, dynamin, and the htt binding partners htt interacting protein 1 (HIP1), SH3-containing Grb2-like protein (SH3GL3), and 14.7K-interacting protein were reduced in their normal location and redistributed to the shell. Removal of a series of prolines adjacent to the polyglutamine region in htt blocked formation of the shell of the htt body and redistribution of dynamin, HIP1, SH3GL3, and proteasome to it. Internalization of transferrin was impaired in cells that formed htt bodies. In cortical neurons of Huntington's disease patients with early stage pathology, dynamin immunoreactivity accumulated in cytoplasmic bodies. Results suggest that accumulation of a nonfibrillar form of mutant htt in the cytoplasm contributes to neuronal dysfunction by sequestering proteins involved in vesicle trafficking.

Key words: Huntington's disease; huntingtin; autophagy; vesicle trafficking; dynamin; protein aggregates; protein interactions

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Received May 9, 2003; revised October 1, 2003; accepted October 20, 2003.

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