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 Ca²⁺ homeostasis. Using temperature-sensitive SEC4 mutants and deletion strains for the vacuolar Ca²⁺ transporters Pmc1 and Vcx1, together with aequorin-based Ca²⁺ recordings, we show that overexpression of α-syn shifts the predominant temporal pattern of organellar Ca²⁺ 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 Ca²⁺. α-Syn further significantly reduced Ca²⁺ storage resulting in increased resting cytosolic Ca²⁺ levels. Overexpression of the vacuolar Ca²⁺ ATPase Pmc1 in wild-type cells prevented the α-syn-induced increase in resting Ca²⁺ and was able to restore growth. We propose that α-syn-induced disruptions in Ca²⁺ signaling might be an important step in initiating cell death.

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Journal Article

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Callewaert G, D'hooge P, Ma TY, Del Vecchio M, Van Eyck V, Franssens V, Winderickx J

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