Soste, Martin, Charmpi, Konstantina, Lampert, Fabienne, Gerez, Juan Atilio, van Oostrum, Marc ORCID: 0000-0001-8747-9787, Malinovska, Liliana, Boersema, Paul Jonathan, Prymaczok, Natalia Cecilia, Riek, Roland, Peter, Matthias, Vanni, Stefano ORCID: 0000-0003-2146-1140, Beyer, Andreas ORCID: 0000-0002-3891-2123 and Picotti, Paola (2019). Proteomics-Based Monitoring of Pathway Activity Reveals that Blocking Diacylglycerol Biosynthesis Rescues from Alpha-Synuclein Toxicity. Cell Syst., 9 (3). S. 309 - 329. CAMBRIDGE: CELL PRESS. ISSN 2405-4720

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Abstract

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.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Soste, MartinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Charmpi, KonstantinaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lampert, FabienneUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gerez, Juan AtilioUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
van Oostrum, MarcUNSPECIFIEDorcid.org/0000-0001-8747-9787UNSPECIFIED
Malinovska, LilianaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Boersema, Paul JonathanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Prymaczok, Natalia CeciliaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Riek, RolandUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Peter, MatthiasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Vanni, StefanoUNSPECIFIEDorcid.org/0000-0003-2146-1140UNSPECIFIED
Beyer, AndreasUNSPECIFIEDorcid.org/0000-0002-3891-2123UNSPECIFIED
Picotti, PaolaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-133678
DOI: 10.1016/j.cels.2019.07.010
Journal or Publication Title: Cell Syst.
Volume: 9
Number: 3
Page Range: S. 309 - 329
Date: 2019
Publisher: CELL PRESS
Place of Publication: CAMBRIDGE
ISSN: 2405-4720
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
PAH1 PHOSPHATIDATE PHOSPHATASE; SACCHAROMYCES-CEREVISIAE; LIPID DROPLETS; PHOSPHOLIPID BIOSYNTHESIS; ORTHOLOGUE PAH1P; YEAST; PROTEIN; PHOSPHORYLATION; GENE; AGGREGATIONMultiple languages
Biochemistry & Molecular Biology; Cell BiologyMultiple languages
Refereed: Yes
URI: http://kups.ub.uni-koeln.de/id/eprint/13367

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