title: Degradation of mutant huntingtin via the ubiquitin/proteasome system is modulated by FE65.
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 Htt in cells by preventing its degradation via the UPS, and thereby enhances the toxicity of mutant Htt.
authors.affiliation: School of Life Sciences, Faculty of Science, The Chinese University of Hong Kong, Shatin, NT, Hong Kong.
authors.forename: Wan Ning Vanessa
authors.initials: WN
authors.lastname: Chow
authors.forename: Hon Wing
authors.initials: HW
authors.lastname: Luk
authors.forename: Ho Yin Edwin
authors.initials: HY
authors.lastname: Chan
authors.forename: Kwok-Fai
authors.initials: KF
authors.lastname: Lau
mesh_terms: D000818:Animals; D001483:Base Sequence; D002460:Cell Line; D017931:DNA Primers; D019084:Fluorescent Antibody Technique, Indirect; D006801:Humans; D000071058:Huntingtin Protein; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D059748:Proteolysis; D025801:Ubiquitin / Q000378:metabolism*; D054875:Ubiquitination
chemical_list: C091042:APBB1 protein, human; D017931:DNA Primers; C086055:HTT protein, human; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D025801:Ubiquitin; D046988:Proteasome Endopeptidase Complex