Proteomics-Based Monitoring of Pathway Activity Reveals that Blocking Diacylglycerol Biosynthesis Rescues from Alpha-Synuclein Toxicity

被引：16

作者：

Soste, Martin ^{[1
,2
,7
]}

Charmpi, Konstantina ^{[3
,4
]}

Lampert, Fabienne ^{[1
]}

Gerez, Juan Atilio ^{[5
]}

van Oostrum, Marc ^{[1
,8
]}

Malinovska, Liliana ^{[1
,2
]}

Boersema, Paul Jonathan ^{[1
,2
]}

Prymaczok, Natalia Cecilia ^{[5
]}

Riek, Roland ^{[5
]}

Peter, Matthias ^{[1
]}

Vanni, Stefano ^{[6
]}

Beyer, Andreas ^{[3
,4
]}

Picotti, Paola ^{[1
,2
]}

机构：

[1] Swiss Fed Inst Technol, Dept Biol, Inst Biochem, Zurich, Switzerland

[2] Swiss Fed Inst Technol, Inst Mol Syst Biol, Dept Biol, Zurich, Switzerland

[3] Univ Cologne, CECAD, Cologne, Germany

[4] Univ Cologne, CMMC, Cologne, Germany

[5] Swiss Fed Inst Technol, Dept Chem & Appl Biosci, Lab Phys Chem, Zurich, Switzerland

[6] Univ Fribourg, Dept Biol, Fribourg, Switzerland

[7] Univ Toronto, Donnelly Ctr Cellular & Biomol Res, Toronto, ON, Canada

[8] Swiss Fed Inst Technol, Dept Hlth Sci & Technol, Dept Biol & Biomed Prote Platform, Inst Mol Syst Biol, Zurich, Switzerland

来源：

CELL SYSTEMS | 2019年 / 9卷 / 03期

基金：

欧洲研究理事会; 瑞士国家科学基金会;

关键词：

PAH1 PHOSPHATIDATE PHOSPHATASE; SACCHAROMYCES-CEREVISIAE; LIPID DROPLETS; PHOSPHOLIPID BIOSYNTHESIS; ORTHOLOGUE PAH1P; YEAST; PROTEIN; PHOSPHORYLATION; GENE; AGGREGATION;

D O I：

10.1016/j.cels.2019.07.010

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：

Proteinaceous inclusions containing alpha-synuclein (alpha-Syn) have been implicated in neuronal toxicity in Parkinson's disease, but the pathways that modulate toxicity remain enigmatic. Here, we used a targeted proteomic assay to simultaneously measure 269 pathway activation markers and proteins deregulated by alpha-Syn expression across a panel of 33 Saccharomyces cerevisiae strains that genetically modulate alpha-Syn toxicity. Applying multidimensional linear regression analysis to these data predicted Pah1, a phosphatase that catalyzes conversion of phosphatidic acid to diacylglycerol at the endoplasmic reticulum membrane, as an effector of rescue. Follow-up studies demonstrated that inhibition of Pahl activity ameliorates the toxic effects of alpha-Syn, indicate that the diacylglycerol branch of lipid metabolism could enhance alpha-Syn neuronal cytotoxicity, and suggest a link between alpha-Syn toxicity and the biology of lipid droplets.

引用

页码：309 / +

页数：20

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