Calcineurin determines toxic versus beneficial responses to α-synuclein

• DOI: 10.1073/pnas.1413201111
• Publication Date: 2014-08-14T04:10:36Z
• Authors: Gabriela Caraveo; Pavan K. Auluck; Luke Whitesell; Chee Yeun Chung; Valeriya Baru; Eugene V. Mosharov; Xiaohui Yan; Manu Ben-Johny; Martin Soste; Paola Picotti; Hanna Kim; Kim A. Caldwell; Guy A. Caldwell; David Sulzer; David T. Yue; Susan Lindquist
• Keywords: Synucleinopathies; Homeostasis

Significance Ca 2+ homeostasis is indispensable for the well being of all living organisms. disrupted by α-synuclein (α-syn), whose misfolding plays a major role in neurodegenerative diseases termed synucleinopathies, such as Parkinson disease. We report that α-syn can induce sustained and highly elevated levels cytoplasmic , thereby activating calcineurin (CN) cascade results toxicity. CN conserved –calmodulin (CaM)-dependent phosphatase critical sensing concentrations transducing information into cellular responses. Limiting, but not eliminating, availability CaM, and/or substrates directly with genetic or pharmacological tools shifts α-syn–induced to protective mode. This has mechanistic implications CN's activity provides therapeutic venue treatment synucleinopathies.