Phosphorylation, lipid raft interaction and traffic of α-synuclein in a yeast model for Parkinson

Parkinson's disease is a neurodegenerative disorder characterized by the formation of Lewy bodies containing aggregated (alpha-synuclein. We used a yeast model to screen for deletion mutants with mislocalization and enhanced inclusion formation of u-synuclein. Many of the mutants were affected in functions related to vesicular traffic but especially mutants in endocytosis and vacuolar degradation combined inclusion formation with enhanced (alpha-synuclein-mediated toxicity. The screening also allowed for identification of casein kinases responsible for (alpha-synuclein phosphorylation at the plasma membrane as well as transacetylases that modulate the (alpha-synuclein membrane interaction. In addition, a-synuclein was found to associate with lipid rafts, a phenomenon dependent on the ergosterol content. Together, our data suggest that toxicity of (alpha-synuclein in yeast is at least in part associated with endocytosis of the protein, vesicular recycling back to the plasma membrane and vacuolar fusion defects, each contributing to the obstruction of different vesicular trafficking routes. (c) 2008 Elsevier B.V. All rights reserved.