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The yeast  Saccharomyces cerevisiae  is a powerful model to study the molecular mechanisms underlying α-synuclein (α-syn) cytotoxicity. This is due to the high degree of conservation of cellular processes with higher eukaryotes and the fact that yeast does not endogenously express α-synuclein. In this work, we focused specifically on the interplay between α-syn and intracellular Ca 2+  homeostasis. Using temperature-sensitive  SEC4  mutants and deletion strains for the vacuolar Ca 2+  transporters Pmc1 and Vcx1, together with aequorin-based Ca 2+  recordings, we show that overexpression of α-syn shifts the predominant temporal pattern of organellar Ca 2+  release from a biphasic to a quasi-monophasic response. Fragmentation and vesiculation of vacuolar membranes in α-syn expressing cells can account for the faster release of vacuolar Ca 2+ . α-Syn further significantly reduced Ca 2+  storage resulting in increased resting cytosolic Ca 2+  levels. Overexpression of the vacuolar Ca 2+  ATPase Pmc1 in wild-type cells prevented the α-syn-induced increase in resting Ca 2+  and was able to restore growth. We propose that α-syn-induced disruptions in Ca 2+  signaling might be an important step in initiating cell death.

Decreased Vacuolar Ca2+ Storage and Disrupted Vesicle Trafficking Underlie Alpha-Synuclein-Induced Ca2+ Dysregulation in S. cerevisiae