title: α-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 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.
authors.affiliation: Department of Biochemistry and Molecular Biology, Louisiana State University Health Sciences Center, Shreveport, LA 71130, USA.
authors.forename: Shaoxiao
authors.initials: S
authors.lastname: Wang
authors.forename: Baoshan
authors.initials: B
authors.lastname: Xu
authors.forename: Liang-Chun
authors.initials: LC
authors.lastname: Liou
authors.forename: Qun
authors.initials: Q
authors.lastname: Ren
authors.forename: Shile
authors.initials: S
authors.lastname: Huang
authors.forename: Yan
authors.initials: Y
authors.lastname: Luo
authors.forename: Zhaojie
authors.initials: Z
authors.lastname: Zhang
authors.forename: Stephan N
authors.initials: SN
authors.lastname: Witt
mesh_terms: D000704:Analysis of Variance; D015153:Blotting, Western; D019086:Bridged Bicyclo Compounds, Heterocyclic; D045744:Cell Line, Tumor; D006801:Humans; D008856:Microscopy, Fluorescence; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009410:Nerve Degeneration / Q000378:metabolism / Q000503:physiopathology*; D010300:Parkinson Disease / Q000378:metabolism / Q000503:physiopathology*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D053778:Thiazolidines; D015003:Yeasts; D051844:alpha-Synuclein / Q000378:metabolism* / Q000633:toxicity; D001616:beta-Galactosidase
chemical_list: D019086:Bridged Bicyclo Compounds, Heterocyclic; D053778:Thiazolidines; D051844:alpha-Synuclein; C496126:PLK2 protein, human; D017346:Protein Serine-Threonine Kinases; D020928:Mitogen-Activated Protein Kinases; D001616:beta-Galactosidase; C037067:latrunculin A