1. Proteomics-Based Monitoring of Pathway Activity Reveals that Blocking Diacylglycerol Biosynthesis Rescues from Alpha-Synuclein Toxicity.
- Author
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Soste M, Charmpi K, Lampert F, Gerez JA, van Oostrum M, Malinovska L, Boersema PJ, Prymaczok NC, Riek R, Peter M, Vanni S, Beyer A, and Picotti P
- Subjects
- Apoptosis, Gene Expression Regulation, Fungal, Humans, Lipid Droplets metabolism, Lipid Metabolism, Molecular Targeted Therapy, Signal Transduction, alpha-Synuclein genetics, Galactolipids metabolism, Neurons physiology, Parkinson Disease metabolism, Phosphatidate Phosphatase metabolism, Proteomics methods, Saccharomyces cerevisiae genetics, Saccharomyces cerevisiae Proteins metabolism, alpha-Synuclein metabolism
- Abstract
Proteinaceous inclusions containing alpha-synuclein (α-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 α-Syn expression across a panel of 33 Saccharomyces cerevisiae strains that genetically modulate α-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 Pah1 activity ameliorates the toxic effects of α-Syn, indicate that the diacylglycerol branch of lipid metabolism could enhance α-Syn neuronal cytotoxicity, and suggest a link between α-Syn toxicity and the biology of lipid droplets., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2019
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