Calcineurin stimulation by Cnb1p overproduction mitigates protein aggregation and ?-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 ?-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 ?-Synuclein A53T in a partly CRZ1-dependent manner. Activation of calcineurin boosted normal localization of both wild type and mutant ?-synuclein to the plasma membrane, an intervention previously shown to mitigate ?-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. Video Abstract.
Mesh Terms:
Calcineurin, DNA-Binding Proteins, Humans, Parkinson Disease, Protein Aggregates, Saccharomyces cerevisiae, Saccharomyces cerevisiae Proteins, Synucleinopathies, Transcription Factors, alpha-Synuclein
Cell Commun Signal
Date: Aug. 24, 2023
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