Ca2+ 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 Ca2+, which adjusts intracellular Ca2+ handling and boosts lysosomal proteolysis. Heterologous expression of human alpha-synuclein (alpha Syn), a protein critically linked to Parkinson's disease, selectively increases total cellular Ca2+ content, while the levels of manganese and iron remain unchanged. Disrupted Ca2+ homeostasis results in inhibition of the lysosomal protease cathepsin D and triggers premature cellular and organismal death. External administration of Ca2+ reduces alpha Syn oligomerization, stimulates cathepsin D activity and in consequence restores survival, which critically depends on the Ca2+/calmodulin-dependent phosphatase calcineurin. In flies, increasing the availability of Ca2+ discloses a neuroprotective role of alpha Syn upon manganese overload. In sum, we establish a molecular interplay between cathepsin D and calcineurin that can be activated by Ca2+ administration to counteract alpha Syn proteotoxicity. Author summaryThe accumulation and aggregation of neurotoxic proteins represents a hallmark of age-associated neurodegenerative disorders. Mostly, this is accompanied by a reduction of the cell's capacity to proteolytically remove these aggregation-prone proteins. Thus, stimulation of degradative pathways to clear neurotoxic proteins represents an emerging theme to counteract neurodegeneration. The pathology of Parkinson's disease (PD) is intimately connected to alpha-synuclein aggregation, and alpha-synuclein mutations or increased alpha-synuclein protein levels upon gene duplication cause hereditary PD. Using simple model systems to study alpha-synuclein toxicity, we establish a novel regime that re-activates cellular degradative capacity and prevents alpha-synuclein-induced cellular decline. Specifically, we show that increasing the bioavailability of Ca2+ stimulates protein degradation within the lysosome, the cell's waste bin and recycling facility. Whereas alpha-synuclein compromised cellular Ca2+ homeostasis and reduced the activity of the lysosomal protease cathepsin D, simple administration of extra Ca2+ corrected these defects. We provide insights into the molecular pathways underlying cytoprotection achieved by Ca2+ supplementation and identify a causal role for central calcium signaling pathways in Ca2+-mediated stimulation of cathepsin D activity. In sum, our results establish a regime to improve the cellular capacity to cope with proteotoxic stress that functions across species barriers and might be transferable to other neurotoxic proteins.