Phosphorylation, lipid raft interaction and traffic of alpha-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 alpha-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, alpha-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.
Zabrocki
Piotr
P
Laboratory of Functional Biology, Kasteelpark Arenberg 31, 3001 Heverlee, Belgium.
Bastiaens
Ilse
I
Delay
Charlotte
C
Bammens
Tine
T
Ghillebert
Ruben
R
Pellens
Klaartje
K
De Virgilio
Claudio
C
Van Leuven
Fred
F
Winderickx
Joris
J
D047388:Casein Kinases / Q000235:genetics / Q000378:metabolism; D004875:Ergosterol / Q000494:pharmacology; D021962:Membrane Microdomains / Q000378:metabolism*; D008954:Models, Biological; D009154:Mutation / Q000235:genetics; D010300:Parkinson Disease / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D021381:Protein Transport; D012441:Saccharomyces cerevisiae / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D013379:Substrate Specificity; D051844:alpha-Synuclein / Q000235:genetics / Q000378:metabolism*
D051844:alpha-Synuclein; D047388:Casein Kinases; D004875:Ergosterol