Clearance of mutant huntingtin.
Clearance of mutant huntingtin.
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DOI：
10.4161/auto.6.5.12336
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发表时间：
2010-07
期刊：
影响因子：
13.3
通讯作者：
Li S
中科院分区：
文献类型：
--
作者：
Li XJ;Li H;Li S
突变型亨廷顿蛋白（htt）在其n端区域携带扩增的聚谷氨酰胺（polyQ）重复序列（bbbb36谷氨酰胺），导致htt错误折叠并杀死亨廷顿病（HD）的神经元细胞。通过表达这些htt片段的转基因小鼠的严重神经表型可以明显看出n端突变htt片段的细胞毒性。突变htt的清除主要由泛素-蛋白酶体系统（UPS）和自噬介导。然而，这两种系统去除突变htt的毒性形式的相对效率尚未得到严格的比较。通过HD的细胞和小鼠模型，我们发现抑制UPS导致突变htt的积累比抑制自噬更大。此外，抑制UPS后，HD小鼠大脑中n端突变体htt片段而非全长突变体htt片段积累。这些发现表明，UPS比自噬更有效地去除n端突变体htt。
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.