Calcineurin stimulation by Cnb1p overproduction mitigates protein aggregation and a-synuclein toxicity in a yeast model of synucleinopathy

The calcium-responsive phosphatase, calcineurin, senses changes in Ca2+ concentrations in a calmodulin-dependent manner. Here we report that under non-stress conditions, inactivation of calcineurin signaling or deleting the calcineurin-dependent transcription factor CRZ1 triggered the formation of chaperone Hsp100p (Hsp104p)-associated protein aggregates in Saccharomyces cerevisiae. Furthermore, calcineurin inactivation aggravated a-Synuclein-related cytotoxicity. Conversely, elevated production of the calcineurin activator, Cnb1p, suppressed protein aggregation and cytotoxicity associated with the familial Parkinson's disease-related mutant a-Synuclein A53T in a partly CRZ1-dependent manner. Activation of calcineurin boosted normal localization of both wild type and mutant a-synuclein to the plasma membrane, an intervention previously shown to mitigate a-synuclein toxicity in Parkinson's disease models. The findings demonstrate that calcineurin signaling, and Ca2+ influx to the vacuole, limit protein quality control in non-stressed cells and may have implications for elucidating to which extent aberrant calcineurin signaling contributes to the progression of Parkinson's disease(s) and other synucleinopathies.

Automated summary

Calcineurin senses changes in calcium concentrations and its inactivation triggers chaperone-associated protein aggregates in yeast. Inactivation of calcineurin also worsens α-Synuclein-related cytotoxicity. On the other hand, activation of calcineurin suppresses protein aggregation and cytotoxicity associated with Parkinson's disease-related mutant α-Synuclein in a partly CRZ1-dependent manner, by promoting proper localization of α-synuclein to the plasma membrane.