Huntington toxicity in yeast model depends on polyglutamine aggregation mediated by a prion-like protein Rnq1.
Huntington toxicity in yeast model depends on polyglutamine aggregation mediated by a prion-like protein Rnq1.
复制标题
DOI：
10.1083/jcb.200112104
复制
发表时间：
2002-06-10
期刊：
影响因子：
--
通讯作者：
Sherman MY
中科院分区：
文献类型：
--
作者：
Meriin AB;Zhang X;He X;Newnam GP;Chernoff YO;Sherman MY
亨廷顿病的病因是亨廷顿蛋白中聚谷氨酰胺 (polyQ) 结构域的扩展，这使得该蛋白具有神经毒性且易于聚集。在这里，我们开发了第一个酵母模型，该模型在扩展的 PolyQ 结构域的聚集与其细胞毒性之间建立了直接联系。我们的数据表明，分子伴侣 Sis1 和 Hsp104 的缺陷抑制了 PolyQ 聚集体的播种，而 ssa1、ssa2 和 ydj1-151 突变则抑制了聚集体的扩张。后三个突变体强烈抑制了polyQ的毒性。聚集受到抑制的自发突变体出现频率较高，并且所有突变体的毒性均得到缓解。这些突变体和 sis1-85 中的聚集缺陷在与 hsp104 突变体的杂交中并未得到补充，这表明了一种不寻常的遗传类型。由于 Hsp104 是酵母中朊病毒维持所必需的，这表明朊病毒在 PolyQ 聚集和毒性中发挥作用。我们筛选了一组编码已知朊病毒和相关蛋白的非必需基因的缺失，发现RNQ1基因的缺失特异性抑制了polyQ的聚集和毒性。从野生型细胞中消除朊病毒形式的 Rnq1 可以显着抑制 PolyQ 的聚集和毒性。我们得出的结论是，polyQ 的聚集对其毒性至关重要，而朊病毒构象中的 Rnq1 在导致毒性的 polyQ 聚集中起着至关重要的作用。
The cause of Huntington's disease is expansion of polyglutamine (polyQ) domain in huntingtin, which makes this protein both neurotoxic and aggregation prone. Here we developed the first yeast model, which establishes a direct link between aggregation of expanded polyQ domain and its cytotoxicity. Our data indicated that deficiencies in molecular chaperones Sis1 and Hsp104 inhibited seeding of polyQ aggregates, whereas ssa1, ssa2, and ydj1–151 mutations inhibited expansion of aggregates. The latter three mutants strongly suppressed the polyQ toxicity. Spontaneous mutants with suppressed aggregation appeared with high frequency, and in all of them the toxicity was relieved. Aggregation defects in these mutants and in sis1–85 were not complemented in the cross to the hsp104 mutant, demonstrating an unusual type of inheritance. Since Hsp104 is required for prion maintenance in yeast, this suggested a role for prions in polyQ aggregation and toxicity. We screened a set of deletions of nonessential genes coding for known prions and related proteins and found that deletion of the RNQ1 gene specifically suppressed aggregation and toxicity of polyQ. Curing of the prion form of Rnq1 from wild-type cells dramatically suppressed both aggregation and toxicity of polyQ. We concluded that aggregation of polyQ is critical for its toxicity and that Rnq1 in its prion conformation plays an essential role in polyQ aggregation leading to the toxicity.
登录
查看更多内容
DOI：
10.1083/jcb.143.7.1883
发表时间：
1998-12-28
期刊：
The Journal of cell biology
影响因子：
--
作者：
Johnston JA;Ward CL;Kopito RR
通讯作者：
Kopito RR
影响因子：
6.4
作者：
Bates, GP;Mangiarini, L;Davies, SW
通讯作者：
Davies, SW
影响因子：
56.9
作者：
Patino, MM;Liu, JJ;Lindquist, S
通讯作者：
Lindquist, S
影响因子：
5.3
作者：
Moriyama, H;Edskes, HK;Wickner, RB
通讯作者：
Wickner, RB
影响因子：
56.9
作者：
Kazemi-Esfarjani, P;Benzer, S
通讯作者：
Benzer, S