The Parkinson's disease protein alpha-synuclein is a modulator of processing bodies and mRNA stability

被引：109

作者：

Hallacli, Erinc ^{[1
,2
,3
,4
]}

Kayatekin, Can ^{[4
]}

Nazeen, Sumaiya ^{[1
,2
,3
,5
,6
]}

Wang, Xiou H. ^{[1
,2
,3
]}

Sheinkopf, Zoe ^{[1
,2
,3
]}

Sathyakumar, Shubhangi ^{[1
,2
,3
]}

Sarkar, Souvarish ^{[2
,7
]}

Jiang, Xin ^{[8
]}

Dong, Xianjun ^{[1
,2
,9
,10
]}

Di Maio, Roberto ^{[11
,12
]}

Wang, Wen ^{[13
]}

Keeney, Matthew T. ^{[11
,12
]}

Felsky, Daniel ^{[14
,15
,16
,17
]}

Sandoe, Jackson ^{[4
]}

Vahdatshoar, Aazam ^{[1
,2
,3
]}

Udeshi, Namrata D. ^{[18
]}

Mani, D. R. ^{[18
]}

Carr, Steven A. ^{[18
]}

Lindquist, Susan ^{[4
,19
,20
]}

De Jager, Philip L. ^{[21
]}

Bartel, David P. ^{[4
,19
,20
]}

Myers, Chad L. ^{[13
]}

Greenamyre, J. Timothy ^{[11
,12
]}

Feany, Mel B. ^{[2
,7
]}

Sunyaev, Shamil R. ^{[5
,6
]}

Chung, Chee Yeun

Khurana, Vikram ^{[1
,2
,3
,10
,18
,22
]}

机构：

[1] Brigham & Womens Hosp, Ann Romney Ctr Neurol Dis, Boston, MA 02115 USA

[2] Harvard Med Sch, Boston, MA 02115 USA

[3] Brigham & Womens Hosp, Div Movement Disorders, Dept Neurol, Boston, MA 02115 USA

[4] Whitehead Inst Biomed Res, Cambridge, MA 02142 USA

[5] Harvard Med Sch, Dept Biomed Informat, Boston, MA 02115 USA

[6] Brigham & Womens Hosp, Div Genet, Dept Med, Boston, MA 02115 USA

[7] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA

[8] Yuman Therapeut, Boston, MA 02135 USA

[9] Brigham & Womens Hosp, Genom & Bioinformat Hub, Boston, MA 02115 USA

[10] Aligning Sci Parkinsons ASAP Collaborat Res Netwo, Chevy Chase, MD 20815 USA

[11] Pittsburgh Inst Neurodegenerat Dis, Pittsburgh, PA 15213 USA

[12] Dept Neurol, Pittsburgh, PA 15213 USA

[13] Univ Minnesota, Dept Comp Sci & Engn, Minneapolis, MN 55455 USA

[14] Univ Toronto, Krembil Ctr Neuroinformat, Toronto, ON M5T IR8, Canada

[15] Univ Toronto, Dept Psychiat, Toronto, ON M5T IR8, Canada

[16] Univ Toronto, Temerty Fac Med, Dept Psychiat, 1 Kings Coll Circle, Toronto, ON M5S IA8, Canada

[17] Univ Toronto, Dalla Lana Sch Publ Hlth, Div Biostat, 155 Coll St, Toronto, ON M5T 3M7, Canada

[18] Broad Inst MIT & Harvard, Cambridge, MA 02142 USA

[19] Howard Hughes Med Inst, Cambridge, MA 02142 USA

[20] MIT, Dept Biol, Cambridge, MA 02139 USA

[21] Columbia Univ, Dept Neurol, Ctr Translat Computat Neuroimmunol, Irving Med Ctr, New York, NY 10032 USA

[22] Harvard Stem Cell Inst, Cambridge, MA 02138 USA

来源：

CELL | 2022年 / 185卷 / 12期

关键词：

GENOME-WIDE ASSOCIATION; COGNITIVE IMPAIRMENT; STRESS GRANULES; RUSH MEMORY; RISK LOCI; GENE; IDENTIFICATION; METAANALYSIS; TRAFFICKING; PATHOLOGY;

D O I：

10.1016/j.cell.2022.05.008

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Alpha-synuclein (alpha S) 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 alpha S directly modulates processing bodies (P-bodies), membraneless organelles that function in mRNA turnover and storage. The N terminus of alpha S, but not other synucleins, dictates mutually exclusive binding either to cellular membranes or to P-bodies in the cytosol. alpha S associates with multiple decapping proteins in close proximity on the Edc4 scaffold. As alpha S 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 alpha S toxicity, and human genetic analysis lends support to the disease-relevance of these interactions. Beyond revealing an unexpected aspect of alpha S function and pathology, our data highlight the versatility of conformationally plastic proteins with high intrinsic disorder.

引用

页码：2035 / +

页数：55

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