Department of Human Genetics, Emory University School of Medicine, Atlanta, GA 30322.
Proc Natl Acad Sci U S A. 2014 Apr 15;111(15):5706-11. doi: 10.1073/pnas.1402215111. Epub 2014 Mar 31.
Ubiquitination of misfolded proteins, a common feature of many neurodegenerative diseases, is mediated by different lysine (K) residues in ubiquitin and alters the levels of toxic proteins. In Huntington disease, polyglutamine expansion causes N-terminal huntingtin (Htt) to misfold, inducing neurodegeneration. Here we report that shorter N-terminal Htt fragments are more stable than longer fragments and find differential ubiquitination via K63 of ubiquitin. Aging decreases proteasome-mediated Htt degradation, at the same time increasing K63-mediated ubiquitination and subsequent Htt aggregation in HD knock-in mice. The association of Htt with the K48-specific E3 ligase, Ube3a, is decreased in aged mouse brain. Overexpression of Ube3a in HD mouse brain reduces K63-mediated ubiquitination and Htt aggregation, enhancing its degradation via the K48 ubiquitin-proteasome system. Our findings suggest that aging-dependent Ube3a levels result in differential ubiquitination and degradation of Htt fragments, thereby contributing to the age-related neurotoxicity of mutant Htt.
泛素化的错误折叠的蛋白质，是许多神经退行性疾病的一个共同特征，由不同的赖氨酸（K）残基在泛素和改变的水平有毒蛋白介导。在亨廷顿病，多聚谷氨酰胺扩展导致 N 端亨廷顿（Htt）错折，诱导神经退行性变。在这里，我们报告说，较短的 N 端 Htt 片段比长片段更稳定，发现通过 K63 泛素的差异泛素化。老化降低蛋白酶体介导的 Htt 降解，同时增加 K63 介导的泛素化和随后的 Htt 聚集在 HD 敲入小鼠。与 K48 特异性 E3 连接酶，Ube3a 的 Htt 的协会在老年小鼠脑减少。在 HD 小鼠脑中的 Ube3a 的过表达减少 K63 介导的泛素化和 Htt 聚集，增强其通过 K48 泛素-蛋白酶体系统降解。我们的研究结果表明，年龄依赖性 Ube3a 水平导致 Htt 片段的差异泛素化和降解，从而有助于突变 Htt 的年龄相关的神经毒性。
