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Huntingtin bodies sequester vesicle-associated proteins by a polyproline-dependent interaction

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Item Type:Article
Title:Huntingtin bodies sequester vesicle-associated proteins by a polyproline-dependent interaction
Creators Name:Qin, Z.H. and Wang, Y. and Sapp, E. and Cuiffo, B. and Wanker, E. and Hayden, M.R. and Kegel, K.B. and Aronin, N. and DiFiglia, M.
Abstract: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.
Keywords:Huntington's Disease, Huntingtin, Autophagy, Vesicle Trafficking, Dynamin, Protein Aggregates, Protein Interactions, Animals, Mice
Source:Journal of Neuroscience
ISSN:0270-6474
Publisher:Society for Neuroscience (U.S.A.)
Volume:7
Number:1
Page Range:269-281
Date:7 January 2004
Additional Information:Copyright (c) 2004 by The Society for Neuroscience
Official Publication:https://doi.org/10.1523/JNEUROSCI.1409-03.2004
PubMed:View item in PubMed

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