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

ABSTRACT: Parkinson disease (PD) results from the slow, progressive loss of dopaminergic neurons in the substantia nigra. Alterations in ?-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.

SUBMITTER: Wang S

PROVIDER: S-EPMC3479570 | biostudies-literature | 2012 Oct

REPOSITORIES: biostudies-literature

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

Wang Shaoxiao S Xu Baoshan B Liou Liang-Chun LC Ren Qun Q Huang Shile S Luo Yan Y Zhang Zhaojie Z Witt Stephan N SN

Proceedings of the National Academy of Sciences of the United States of America 20120917 40

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 C ...[more]

PMID: 22988096

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