Department of Neurology, University of Michigan, Ann Arbor, MI 48109, USA; Neuroscience Program, University of Michigan, Ann Arbor, MI 48109, USA; Department of Dermatology, Ruijin Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China.
Department of Neurology, University of Michigan, Ann Arbor, MI 48109, USA; Department of Neurology, Sichuan Provincial Academy of Medical Sciences and Sichuan Provincial People's Hospital, Chengdu, China.
Neurobiol Dis. 2018 Jan;109(Pt A):127-136. doi: 10.1016/j.nbd.2017.10.002. Epub 2017 Oct 3.
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.
亨廷顿病（HD）是由编码亨廷顿病蛋白（HTT）中多聚谷氨酰胺（polyQ）扩展的 CAG 重复扩展引起的。polyQ 扩展促进突变 HTT（mHTT）在神经元内的错误折叠和聚集。mHTT 受调节的细胞途径，包括泛素依赖性过程，仍不完全了解。Ube2W 是唯一已知的将泛素连接酶（E2）连接到其氨基（N）末端的泛素连接酶，可能有利于具有无序 N 末端的底物。由于其 N 端 polyQ 结构域，HTT 具有固有无序的氨基末端。在使用永生化细胞、原代神经元和 HD 的敲入（KI）小鼠模型进行的研究中，我们测试了 Ube2W 缺乏对 mHTT 水平、聚集和神经毒性的影响。在培养细胞中，Ube2W 活性的缺乏显著减少 mHTT 聚集体的形成并增加可溶性单体的水平，同时降低 mHTT 诱导的细胞毒性。与该结果一致，在 HdhQ200 KI 小鼠中缺乏 Ube2W 显著增加可溶性单体形式的 mHTT 水平，同时减少不溶性寡聚体。这项研究阐明了非典型泛素连接酶 Ube2W 在这种 polyQ 神经退行性疾病中的潜在功能。
