The ubiquitin conjugating enzyme Ube2W regulates solubility of the Huntington's disease protein, huntingtin

NEUROBIOLOGY OF DISEASE

卷:109

Article

Wang, Bo^1,2,3  Zeng, Li^1,4,5  Merillat, Sean A.¹  Fischer, Svetlana¹  Ochaba, Joseph^6,7  Thompson, Leslie M.^6,7  Barmada, Sami J.¹  Scaglione, Kenneth M.^8,9  Paulsona, Henry L.^1,2 

[1] Univ Michigan, Dept Neurol, Ann Arbor, MI 48109 USA

[2] Univ Michigan, Neurosci Program, Ann Arbor, MI 48109 USA

[3] Shanghai Jiao Tong Univ, Ruijin Hosp, Sch Med, Dept Dermatol, Shanghai, Peoples R China

[4] Sichuan Prov Acad Med Sci, Dept Neurol, Chengdu, Sichuan, Peoples R China

[5] Sichuan Prov Peoples Hosp, Chengdu, Sichuan, Peoples R China

[6] Univ Calif Irvine, Dept Neurobiol & Behav, Inst Memory Impairment & Neurol Disorders, Irvine, CA 92697 USA

[7] Univ Calif Irvine, Inst Memory Impairment & Neurol Disorders, Dept Psychiat & Human Behav, Irvine, CA 92697 USA

[8] Med Coll Wisconsin, Neurosci Res Ctr, Milwaukee, WI 53226 USA

[9] Med Coll Wisconsin, Dept Biochem, Milwaukee, WI 53226 USA

关键词: Huntington's disease;    Huntingtin;    Ubiquitination;    Ubiquitin-conjugating enzyme;    Ube2W;    Protein misfolding;    Neurodegeneration;   

DOI  :  10.1016/j.nbd.2017.10.002

来源: Elsevier

【 摘 要 】

Huntington's disease (HD) is caused by a CAG repeat expansion that encodes a polyglutamine (polyQ) expansion in the HD disease protein, huntingtin (HTT). PolyQ expansion promotes misfolding and aggregation of mutant HTT (mHTT) within neurons. The cellular pathways, including ubiquitin-dependent processes, by which mHTT is regulated remain incompletely understood. Ube2W is the only ubiquitin conjugating enzyme (E2) known to ubiquitinate substrates at their amino (N)-termini, likely favoring substrates with disordered N-termini. By virtue of its N-terminal polyQ domain, HTT has an intrinsically disordered amino terminus. In studies employing immortalized cells, primary neurons and a knock-in (KI) mouse model of HD, we tested the effect of Ube2W deficiency on mHTT levels, aggregation and neurotoxicity. In cultured cells, deficiency of Ube2W activity markedly decreases mHTT aggregate formation and increases the level of soluble monomers, while reducing mHTT-induced cytotoxicity. Consistent with this result, the absence of Ube2W in HdhQ200 KI mice significantly increases levels of soluble monomeric mHTT while reducing insoluble oligomeric species. This study sheds light on the potential function of the non-canonical ubiquitin-conjugating enzyme, Ube2W, in this polyQ neurodegenerative disease.

【 授权许可】

Free