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Proteomics-Based Monitoring of Pathway Activity Reveals that Blocking Diacylglycerol Biosynthesis Rescues from Alpha-Synuclein Toxicity

Authors
  • Soste, Martin1, 2
  • Charmpi, Konstantina3, 4
  • Lampert, Fabienne1
  • Gerez, Juan Atilio5
  • van Oostrum, Marc1
  • Malinovska, Liliana1, 2
  • Boersema, Paul Jonathan1, 2
  • Prymaczok, Natalia Cecilia5
  • Riek, Roland5
  • Peter, Matthias1
  • Vanni, Stefano6
  • Beyer, Andreas3, 4
  • Picotti, Paola1, 2
  • 1 Institute of Biochemistry, Department of Biology, ETH Zurich, Zurich, Switzerland
  • 2 Institute of Molecular Systems Biology, Department of Biology, ETH Zurich, Zurich, Switzerland
  • 3 CECAD, University of Cologne, Cologne, Germany
  • 4 Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany
  • 5 Laboratory of Physical Chemistry, Department of Chemistry and Applied Biosciences, ETH Zurich, Zurich, Switzerland
  • 6 Department of Biology, University of Fribourg, Fribourg, Switzerland
Type
Published Article
Journal
Cell Systems
Publisher
Cell Press
Publication Date
Sep 25, 2019
Volume
9
Issue
3
Pages
309–320
Identifiers
DOI: 10.1016/j.cels.2019.07.010
PMID: 31521608
PMCID: PMC6859835
Source
PubMed Central
Keywords
License
Unknown

Abstract

α-Synuclein is genetically and neuropathologically linked to Parkinson’s disease. However, the mechanisms of known genetic toxicity modulators in a yeast model system remain largely unknown. In order to identify cellular rescue pathways at high-throughput, we have paired mass spectrometry-based monitoring of pathway activity and growth profiles through regression analysis. The results predicted a critical role for the protein Pah1 in lipid metabolism. Indeed, specific perturbation of Pah1 activity determines inclusion formation and toxicity thereby suggesting a potential target for combating pathologies associated with α-Synuclein accumulation.

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