Journal article

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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 -
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    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
  • English
Classification
Biology
License
License undefined
Identifiers
Persistent URL
https://folia.unifr.ch/unifr/documents/308112
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