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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 RIS Download

Mesh terms: Analysis of Variance | Blotting, Western | Bridged Bicyclo Compounds, Heterocyclic | 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

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Associated grants

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

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