Degradation of mutant huntingtin via the ubiquitin/proteasome system is modulated by FE65

The Biochemical Journal
Wan Ning Vanessa ChowKwok-Fai Lau

Abstract

An unstable expansion of the polyglutamine repeat within exon 1 of the protein Htt (huntingtin) causes HD (Huntington's disease). Mounting evidence shows that accumulation of N-terminal mutant Htt fragments is the source of disruption of normal cellular processes which ultimately leads to neuronal cell death. Understanding the degradation mechanism of mutant Htt and improving its clearance has emerged as a new direction in developing therapeutic approaches to treat HD. In the present study we show that the brain-enriched adaptor protein FE65 is a novel interacting partner of Htt. The binding is mediated through WW-polyproline interaction and is dependent on the length of the polyglutamine tract. Interestingly, a reduction in mutant Htt protein level was observed in FE65-knockdown cells, and the process requires the UPS (ubiquitin/proteasome system). Moreover, the ubiquitination level of mutant Htt was found to be enhanced when FE65 is knocked down. Immunofluroescence staining revealed that FE65 associates with mutant Htt aggregates. Additionally, we demonstrated that overexpression of FE65 increases mutant Htt-induced cell death both in vitro and in vivo. These results suggest that FE65 facilitates the accumulation of mutant Ht...Continue Reading

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Citations

Jul 9, 2014·Evidence-based Complementary and Alternative Medicine : ECAM·Marcel Stark, Christian Behl
Apr 8, 2014·Proceedings of the National Academy of Sciences of the United States of America·Kavita P BhatXiao-Jiang Li
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Sep 24, 2013·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Hei Nga Maggie CheungKwok-Fai Lau
Jul 22, 2018·EMBO Reports·Zhefan Stephen ChenHo Yin Edwin Chan
Jun 18, 2019·Experimental Biology and Medicine·Irina Matlahov, Patrick Ca van der Wel
Oct 14, 2020·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Wai Wa Ray ChanKwok-Fai Lau

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