Proteomics-based monitoring of pathway activity reveals that blocking diacylglycerol biosynthesis rescues from alpha-synuclein toxicity

Soste, Martin; Charmpi, Konstantina; Lampert, Fabienne; Gerez, Juan Atilio; Oostrum, Marcvan; Malinovska, Liliana; Boersema, Paul Jonathan; Prymaczok, Natalia Cecilia; Riek, Roland; Peter, Matthias; Vanni, Stefano; Beyer, Andreas; Picotti, Paola

doi:10.1016/j.cels.2019.07.010

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Proteomics-based monitoring of pathway activity reveals that blocking diacylglycerol biosynthesis rescues from alpha-synuclein toxicity

Soste, Martin Institute of Biochemistry, Department of Biology, ETH Zurich, Switzerland - Institute of Molecular Systems Biology, Department of Biology, ETH Zurich, Switzerland -
Charmpi, Konstantina CECAD, University of Cologne, Germany - Center for Molecular Medicine Cologne (CMMC), University of Cologne, Germany
Lampert, Fabienne Institute of Biochemistry, Department of Biology, ETH Zurich, Switzerland
Gerez, Juan Atilio Laboratory of Physical Chemistry, Department of Chemistry and Applied Biosciences, ETH Zurich, Switzerland
Oostrum, Marcvan Institute of Biochemistry, Department of Biology, ETH Zurich, Switzerland -
Malinovska, Liliana Institute of Biochemistry, Department of Biology, ETH Zurich, Switzerland - Institute of Molecular Systems Biology, Department of Biology, ETH Zurich, Switzerland
Boersema, Paul Jonathan Institute of Biochemistry, Department of Biology, ETH Zurich, Switzerland - Institute of Molecular Systems Biology, Department of Biology, ETH Zurich, Switzerland
Prymaczok, Natalia Cecilia Laboratory of Physical Chemistry, Department of Chemistry and Applied Biosciences, ETH Zurich, Switzerland
Riek, Roland Laboratory of Physical Chemistry, Department of Chemistry and Applied Biosciences, ETH Zurich, Switzerland
Peter, Matthias Institute of Biochemistry, Department of Biology, ETH Zurich, Switzerland
Vanni, Stefano Department of Biology, University of Fribourg, Switzerland
Beyer, Andreas CECAD, University of Cologne, Germany - Center for Molecular Medicine Cologne (CMMC), University of Cologne, Germany
Picotti, Paola Institute of Biochemistry, Department of Biology, ETH Zurich, Switzerland - Institute of Molecular Systems Biology, Department of Biology, ETH Zurich, Switzerland -

25.09.2019

Published in:

Cell Systems. - 2019, vol. 9, no. 3, p. 309-320.e8

English 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.

Faculty

Faculté des sciences et de médecine

Department

Département de Biologie

Language