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α-Synuclein disrupts stress signaling by inhibiting polo-like kinase Cdc5/Plk2.

Parkinson disease (PD) results from the slow, progressive loss of dopaminergic neurons in the substantia nigra. Alterations in α-synuclein (aSyn), such as mutations or multiplications of the gene, are thought to trigger this degeneration. Here, we show that aSyn disrupts mitogen-activated protein kinase (MAPK)-controlled stress signaling in yeast and human cells, which results in inefficient cell protective responses and cell death. aSyn is a substrate of the yeast (and human) polo-like kinase Cdc5 (Plk2), and elevated levels of aSyn prevent Cdc5 from maintaining a normal level of GTP-bound Rho1, which is an essential GTPase that regulates stress signaling. The nine N-terminal amino acids of aSyn are essential for the interaction with polo-like kinases. The results support a unique mechanism of PD pathology.

Pubmed ID: 22988096


  • Wang S
  • Xu B
  • Liou LC
  • Ren Q
  • Huang S
  • Luo Y
  • Zhang Z
  • Witt SN


Proceedings of the National Academy of Sciences of the United States of America

Publication Data

October 2, 2012

Associated Grants

  • Agency: NINDS NIH HHS, Id: NS057656
  • Agency: NINDS NIH HHS, Id: R01 NS057656

Mesh Terms

  • Analysis of Variance
  • Bicyclo Compounds, Heterocyclic
  • Blotting, Western
  • Cell Line, Tumor
  • Humans
  • Microscopy, Fluorescence
  • Mitogen-Activated Protein Kinases
  • Nerve Degeneration
  • Parkinson Disease
  • Protein-Serine-Threonine Kinases
  • Signal Transduction
  • Thiazolidines
  • Yeasts
  • alpha-Synuclein
  • beta-Galactosidase