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Multiple tethers of organelle contact sites are involved in α-synuclein toxicity in yeast

Mara Del Vecchio1,2, Lucia Amado3, Alexandra P Cogan3

  • 1Department of Biology, Functional Biology Laboratory, KU Leuven, 3001 Heverlee, Belgium.

Molecular Biology of the Cell
|April 19, 2023
PubMed

Insights

Organelle contact sites influence Parkinson's disease protein alpha-synuclein (α-syn) toxicity. Disrupting specific membrane tethers increases resistance to α-syn, suggesting a role for interorganelle communication in disease pathology.

Area of Science:

  • Cell Biology
  • Neuroscience
  • Biochemistry

Background:

  • Alpha-synuclein (α-syn) misfolding and aggregation are central to Parkinson's disease (PD) pathogenesis.
  • The precise mechanisms linking α-syn pathology to neuronal dysfunction are not fully understood.
  • Emerging evidence suggests that organelle contact sites play a role in neurodegenerative diseases.

Purpose of the Study:

  • To investigate the role of organelle contact sites in α-syn-mediated cytotoxicity using the model organism *Saccharomyces cerevisiae*.
  • To identify specific proteins and tethers at organelle contact sites that influence α-syn toxicity.

Main Methods:

  • Utilized budding yeast (*Saccharomyces cerevisiae*) as a model system for studying organelle contact sites.
  • Assessed α-syn cytotoxicity in yeast strains with genetic modifications affecting organelle tethers and contact site proteins.
  • Differentiated the roles of protein functions in contact site tethering versus other cellular processes (e.g., protein biogenesis, vesicular transport).

Main Results:

  • Deletion of tethers anchoring the endoplasmic reticulum to the plasma membrane conferred resistance to α-syn expression.
  • Yeast strains lacking Mdm10 or Vps39 proteins showed resistance to α-syn toxicity.
  • Mdm10's role in mitochondrial protein biogenesis, not its tethering function, mediated this resistance.
  • Vps39's functions in vesicular transport and vacuole-mitochondria contact site tethering were both crucial for supporting α-syn toxicity.

Conclusions:

  • Interorganelle communication, particularly through membrane contact sites, is significantly involved in α-syn-mediated toxicity.
  • Specific proteins like Vps39 at contact sites are key regulators of α-syn cytotoxicity.
  • Understanding these interactions may offer new therapeutic targets for Parkinson's disease.

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