PIN1 Modulates Huntingtin Levels and Aggregate Accumulation: An In vitro Model.
PIN1 Modulates Huntingtin Levels and Aggregate Accumulation: An In vitro Model.
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DOI：
10.3389/fncel.2017.00121
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发表时间：
2017
影响因子：
5.3
通讯作者：
Agostoni E
中科院分区：
文献类型：
--
作者：
Carnemolla A;Michelazzi S;Agostoni E
亨廷顿病 (HD) 是一种显性遗传性神经退行性疾病，其特征是亨廷顿蛋白 (HTT) N 末端区域内的聚谷氨酰胺扩张。促进突变亨廷顿蛋白 (mHTT) 清除的细胞机制在 HD 病理学中引起了极大的兴趣，因为它们可以降低突变蛋白及其有毒聚集物质的水平，从而影响疾病的发作和进展。我们之前已经使用遗传精确的 HD 小鼠模型（即 HdhQ111 小鼠）证明，脯氨酰异构酶 PIN1 代表了 mHTT 聚集体积累的有前途的负调节因子。因此，当前的研究旨在支持 PIN1 影响亨廷顿蛋白聚集体的机制。我们发现 PIN1 过表达导致 HEK293 细胞中 mHTT 聚集体减少，这可能与 PIN1 对 mHTT 半衰期的负调节有关。此外，我们表明 PIN1 具有刺激蛋白酶体的能力，这证明了调节这种现象的机制。我们的研究结果为未来对 PIN1 的研究提供了理论依据，并有可能开发出新的治疗策略。
Huntington's disease (HD) is a dominantly inherited neurodegenerative disorder characterized by a polyglutamine expansion within the N-terminal region of huntingtin protein (HTT). Cellular mechanisms promoting mutant huntingtin (mHTT) clearance are of great interest in HD pathology as they can lower the level of the mutant protein and its toxic aggregated species, thus affecting disease onset and progression. We have previously shown that the prolyl-isomerase PIN1 represents a promising negative regulator of mHTT aggregate accumulation using a genetically precise HD mouse model, namely HdhQ111 mice. Therefore, the current study aims at underpinning the mechanism by which PIN1 affects huntingtin's aggregates. We found that PIN1 overexpression led to a reduction of mHTT aggregates in HEK293 cells, and that this could be linked to a negative regulation of mHTT half-life by PIN1. Furthermore, we show that PIN1 has the ability to stimulate the proteasome presenting evidence of a mechanism regulating this phenomenon. Our findings provide a rationale for future investigation into PIN1 with the potential for the development of novel therapeutic strategies.