Ca(2+) administration prevents α-synuclein proteotoxicity by stimulating calcineurin-dependent lysosomal proteolysis

The capacity of a cell to maintain proteostasis progressively declines during aging. Virtually all age-associated neurodegenerative disorders associated with aggregation of neurotoxic proteins are linked to defects in the cellular proteostasis network, including insufficient lysosomal hydrolysis. Here, we report that proteotoxicity in yeast and Drosophila models for Parkinson’s disease can be prevented by increasing the bioavailability of Ca(2+), which adjusts intracellular Ca(2+) handling and boosts lysosomal proteolysis. Heterologous expression of human α-synuclein (αSyn), a protein critically linked to Parkinson’s disease, selectively increases total cellular Ca(2+) content, while the levels of manganese and iron remain unchanged. Disrupted Ca(2+) homeostasis results in inhibition of the lysosomal protease cathepsin D and triggers premature cellular and organismal death. External administration of Ca(2+) reduces αSyn oligomerization, stimulates cathepsin D activity and in consequence restores survival, which critically depends on the Ca(2+)/calmodulin-dependent phosphatase calcineurin. In flies, increasing the availability of Ca(2+) discloses a neuroprotective role of αSyn upon manganese overload. In sum, we establish a molecular interplay between cathepsin D and calcineurin that can be activated by Ca(2+) administration to counteract αSyn proteotoxicity.