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Human Molecular Genetics Advance Access published online on August 18, 2007
Human Molecular Genetics, doi:10.1093/hmg/ddm217
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© 2007 The Author(s)
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Huntingtin Has a Membrane Association Signal that Can Modulate Huntingtin Aggregation, Nuclear Entry and Toxicity

Randy Singh Atwal1, Jianrun Xia1, Deborah Pinchev1, Jillian Taylor1, Richard M. Epand2 and Ray Truant1,*

1 McMaster University, Department of Biochemistry and Biomedical Sciences, HSC 4H24A, 1200 Main Street West, Hamilton, Ontario, Canada, L8N3Z5. 905-525-9140, ex22450. Fax 905-522-9033 2 McMaster University, Department of Biochemistry and Biomedical Sciences, HSC 4H28, 1200 Main Street West, Hamilton, Ontario, Canada, L8N3Z5

* to whom correspondence should be addressed, truantr{at}mcmaster.ca

Received June 26, 2007; Revised July 31, 2007; Accepted July 31, 2007

Huntington's disease (HD) is caused by an expanded polyglutamine tract in huntingtin protein, leading to accumulation of huntingtin in the nuclei of striatal neurons. The 18 amino-acid amino-terminus of huntingtin is an amphipathic alpha helical membrane binding domain that can reversibly target to vesicles and the endoplasmic reticulum (ER). The association of huntingtin to the ER is affected by ER stress. A single point mutation in huntingtin 1-18 predicted to disrupt this helical structure displayed striking phenotypes of complete inhibition of polyglutamine-mediated aggregation, increased huntingtin nuclear accumulation, and greatly increased mutant huntingtin toxicity in a striatal-derived mouse cell line. Huntingtin vesicular interaction mediated by 1-18 is specific to late endosomes and autophagic vesicles. We propose that huntingtin has a normal biological function as an ER-associated protein that can translocate to the nucleus and back out in response to ER stress or other events. The increased nuclear entry of mutant huntingtin due to loss of ER-targeting results in increased toxicity.


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