Proteomics-Based Monitoring of Pathway Activity Reveals that Blocking Diacylglycerol Biosynthesis Rescues from Alpha-Synuclein Toxicity
Gerez, Juan A.
van Oostrum, Marc
Boersema, Paul J.
Prymaczok, Natalia C.
- Journal Article
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. Show more
Journal / seriesCell Systems
Pages / Article No.
Organisational unit03782 - Riek, Roland / Riek, Roland
03595 - Peter, Matthias / Peter, Matthias
03927 - Picotti, Paola / Picotti, Paola
133670 - Understanding the mechanisms of cytotoxic response to aberrantly-folded and aggregated proteins (SNF)
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