The Parkinson's disease protein alpha-synuclein is a modulator of processing bodies and mRNA stability.
The Parkinson's disease protein alpha-synuclein is a modulator of processing bodies and mRNA stability.
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DOI：
10.1016/j.cell.2022.05.008
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发表时间：
2022-06-09
期刊：
影响因子：
64.5
通讯作者：
Khurana, Vikram
中科院分区：
文献类型：
--
作者：
Hallacli, Erinc;Kayatekin, Can;Nazeen, Sumaiya;Wang, Xiou H.;Sheinkopf, Zoe;Sathyakumar, Shubhangi;Sarkar, Souvarish;Jiang, Xin;Dong, Xianjun;Di Maio, Roberto;Wang, Wen;Keeney, Matthew T.;Felsky, Daniel;Sandoe, Jackson;Vahdatshoar, Aazam;Udeshi, Namrata D.;Mani, D. R.;Carr, Steven A.;Lindquist, Susan;De Jager, Philip L.;Bartel, David P.;Myers, Chad L.;Greenamyre, J. Timothy;Feany, Mel B.;Sunyaev, Shamil R.;Chung, Chee Yeun;Khurana, Vikram
α-突触核蛋白（α S）是一种构象可塑性蛋白，可逆地结合到细胞膜上。它聚集并与帕金森病（PD）遗传相关。在这里，我们表明α S直接调节加工体（P体），无膜细胞器，在mRNA的周转和存储功能。α S的N-末端（而不是其他突触核蛋白）决定了与细胞膜或胞质中的P-体的互斥结合。α S与Edc4支架上的多个去帽蛋白紧密结合。随着α S的病理性积累，与Edc4的异常相互作用以生理性去帽模块相互作用为代价发生。PD相关通路内的mRNA衰减动力学在PD患者神经元和脑中相应地被破坏。P体成分的遗传调节改变了α S的毒性，人类遗传分析支持这些相互作用的疾病相关性。除了揭示α S功能和病理学的一个意想不到的方面之外，我们的数据还突出了具有高度内在无序的构象可塑性蛋白质的多功能性。α-突触核蛋白调节mRNA稳定性以调节基因表达，这对理解正常细胞生理学和帕金森病及相关疾病的脆弱性都有意义。
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. Alpha-synuclein modulates mRNA stability to regulate gene expression with implications for understanding both normal cellular physiology and vulnerability to Parkinson’s disease and related disorders.
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DOI：
10.1093/bioinformatics/btu638
发表时间：
2015-01-15
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Anders S;Pyl PT;Huber W
通讯作者：
Huber W
影响因子：
6.1
作者：
Brück D;Wenning GK;Stefanova N;Fellner L
通讯作者：
Fellner L
DOI：
10.3233/jad-179939
发表时间：
2018
期刊：
Journal of Alzheimer's disease : JAD
影响因子：
--
作者：
Bennett DA;Buchman AS;Boyle PA;Barnes LL;Wilson RS;Schneider JA
通讯作者：
Schneider JA
影响因子：
9.8
作者：
Auer, Paul L.;Johnsen, Jill M.;Li, Yun
通讯作者：
Li, Yun
影响因子：
5.4
作者：
Beatman, Erica L.;Massey, Aaron;Beckham, J. David
通讯作者：
Beckham, J. David