帕金森病蛋白α-突触核蛋白是处理体和 mRNA 稳定性的调节剂。
The Parkinson's disease protein alpha-synuclein is a modulator of processing bodies and mRNA stability.
机构信息
Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA; Division of Movement Disorders, Department of Neurology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA; Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA.
Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA.
出版信息
Cell. 2022 Jun 9;185(12):2035-2056.e33. doi: 10.1016/j.cell.2022.05.008.
Alpha-synuclein (αS) is a conformationally plastic protein that reversibly binds to cellular membranes. It aggregates and is genetically linked to Parkinson's disease (PD). Here, we show that αS directly modulates processing bodies (P-bodies), membraneless organelles that function in mRNA turnover and storage. The N terminus of αS, but not other synucleins, dictates mutually exclusive binding either to cellular membranes or to P-bodies in the cytosol. αS associates with multiple decapping proteins in close proximity on the Edc4 scaffold. As αS pathologically accumulates, aberrant interaction with Edc4 occurs at the expense of physiologic decapping-module interactions. mRNA decay kinetics within PD-relevant pathways are correspondingly disrupted in PD patient neurons and brain. Genetic modulation of P-body components alters αS toxicity, and human genetic analysis lends support to the disease-relevance of these interactions. Beyond revealing an unexpected aspect of αS function and pathology, our data highlight the versatility of conformationally plastic proteins with high intrinsic disorder.
α-突触核蛋白（αS）是一种构象可塑性蛋白，可与细胞膜可逆结合。它会聚集，并与帕金森病（PD）的遗传有关。在这里，我们表明 αS 直接调节细胞质中的无膜细胞器处理体（P 体），该细胞器在 mRNA 周转和存储中发挥作用。αS 的 N 端而非其他突触核蛋白决定了与细胞膜或细胞质中 P 体的相互排斥结合。αS 在 Edc4 支架上与多个去帽蛋白密切相关。随着 αS 病理性积累，与 Edc4 的异常相互作用会损害生理去帽模块相互作用。PD 相关途径中的 mRNA 衰减动力学在 PD 患者神经元和大脑中相应受到破坏。P 体成分的遗传调节会改变 αS 的毒性，而人类遗传分析支持这些相互作用与疾病的相关性。除了揭示 αS 功能和病理学的一个意外方面外，我们的数据还强调了具有高固有无序性的构象可塑性蛋白的多功能性。
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