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Author Notes:

To whom correspondence should be addressed at: Department of Human Genetics, Emory University School of Medicine, Atlanta, GA 30322, USA. Email: sli@emory.edu (S.L.) and Division of Histology and Embryology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China. Email: heli@mails.tjmu.edu.cn (H.L.)

X.L. and C.E.W. contributed equally to this work.


Research Funding:

X.L. is supported in part by the China Scholarship Council. This work was supported by grants of National Institutes of Health AG019206, NS041669 (X.J.L.), NS045016 (S.H.L.), and grant from the National Natural Science Foundation of China 30430260 to H.L.

Inhibiting the ubiquitin-proteasome system leads to preferential accumulation of toxic N-terminal mutant huntingtin fragments


Journal Title:

Human Molecular Genetics


Volume 19, Number 12


, Pages 2445-2455

Type of Work:

Article | Post-print: After Peer Review


An expanded polyglutamine (polyQ) domain in the N-terminal region of huntingtin (htt) causes misfolding and accumulation of htt in neuronal cells and the subsequent neurodegeneration of Huntington's disease (HD). Clearing the misfolded htt is critical for preventing neuropathology, and this process is mediated primarily by both the ubiquitin–proteasome system (UPS) and autophagy. Although overexpression of mutant htt can inhibit UPS activity in cultured cells, mutant htt does not inhibit global UPS activity in the brains of HD transgenic mice. These findings underscore the importance of investigating the function of the UPS and autophagy in the brain when mutant proteins are not overexpressed. When cultured PC12 cells were treated with either UPS or autophagy inhibitors, more N-terminal mutant htt fragments accumulated via inhibition of the UPS. Furthermore, in HD CAG repeat knock-in mouse brain, inhibiting the UPS also resulted in a greater accumulation of N-terminal, but not full-length, mutant htt than inhibiting autophagy did. Our findings suggest that impairment of the UPS may be more important for the accumulation of N-terminal mutant htt and might therefore make an attractive therapeutic target.

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© The Author 2010. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

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