latrunculin-a and Nerve-Degeneration

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.

Topics: alpha-Synuclein; Analysis of Variance; beta-Galactosidase; 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