Lake Forest College1, Biology, Lake Forest, IL 60045 Lake Forest College2, Biology, Lake Forest, IL 60045
Parkinson’s disease (PD) is a common, fatal neurodegenerative disease that affects millions. PD is characterized by resting tremors, bradykinesia and postural instability and results from the loss of substantia nigra dopaminergic neurons. The misfolding and aggregation of alpha-synuclein, and its phospholipid binding ability, are linked to both familial and sporadic forms of PD. Three mutations in alpha-synuclein (A30P, A53T and E46K) cause familial PD. Due its more recent discovery, little is known about E46K alpha-synuclein misfolding, aggregation and phospholipid binding properties in live cells. Previously, our lab published fission and budding yeasts as models to study of PD. Using fission yeast, we tested two hypotheses about E46K: (1) It will be toxic to these cells and display both plasma membrane binding and aggregation; and (2) It will aggregate more aggressively than wildtype alpha-synuclein. Indeed, we found that while E46K aggregated more quickly and extensively than wildtype alpha-synuclein, but it was neither toxic to yeast nor did it localize to its plasma membrane. In contrast, in budding yeast, we found that E46K was toxic to some strains, and it bound extensively to yeast plasma membrane without very little aggregation. Put together, the yeast models support the notions that alpha-synuclein plasma membrane localization and cellular toxicity is tightly linked and that alpha-synuclein aggregation is either harmless or protective. Additionally, we propose that fission yeast may lack factors that facilitate alpha-synuclein’s interactions with membrane phospholipids.
S.V. & M.W. were supported by Lake Forest College and by an NIH R15 AREA grant to S.D.
[Abstract (DOC)]