Autophagy. 2010 Jul;6(5):663-4. doi: 10.4161/auto.6.5.12336.
Mutant huntingtin (htt) carries an expanded polyglutamine (polyQ) repeat (> 36 glutamines) in its N-terminal region, which leads htt to become misfolded and kill neuronal cells in Huntington disease (HD). The cytotoxicity of N-terminal mutant htt fragments is evident by severe neurological phenotypes of transgenic mice that express these htt fragments. Clearance of mutant htt is primarily mediated by the ubiquitin-proteasomal sysmtem (UPS) and autophagy. However, the relative efficiency of these two systems to remove toxic forms of mutant htt has not been rigorously compared. Using cellular and mouse models of HD, we found that inhibiting the UPS leads to a greater accumulation of mutant htt than inhibiting autophagy. Moreover, N-terminal mutant htt fragments, but not full-length mutant htt, accumulate in the HD mouse brains after inhibiting the UPS. These findings suggest that the UPS is more efficient than autophagy to remove N-terminal mutant htt.
突变型亨廷顿蛋白（htt）在其 N 端区域携带一个扩展的多聚谷氨酰胺（polyQ）重复序列（>36 个谷氨酰胺），导致 htt 错误折叠并在亨廷顿病（HD）中杀死神经元细胞。表达这些 htt 片段的转基因小鼠的严重神经表型表明 N 端突变型 htt 片段具有细胞毒性。突变型 htt 的清除主要由泛素-蛋白酶体系统（UPS）和自噬介导。然而，这两种系统去除毒性形式的突变型 htt 的相对效率尚未得到严格比较。使用 HD 的细胞和小鼠模型，我们发现抑制 UPS 会导致突变型 htt 的积累比抑制自噬更多。此外，在抑制 UPS 后，突变型 htt 的 N 端片段而不是全长突变型 htt 在 HD 小鼠大脑中积累。这些发现表明 UPS 比自噬更有效地去除 N 端突变型 htt。
