Calcineurin determines toxic versus beneficial responses to α-synuclein

Significance Ca2+ homeostasis is indispensable for the well being of all living organisms. Ca2+ homeostasis is 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 of cytoplasmic Ca2+, thereby activating a calcineurin (CN) cascade that results in toxicity. CN is a highly conserved Ca2+–calmodulin (CaM)-dependent phosphatase critical for sensing Ca2+ concentrations and transducing that information into cellular responses. Limiting, but not eliminating, the availability of CaM, CN and/or CN substrates directly with genetic or pharmacological tools shifts the α-syn–induced CN cascade to a protective mode. This has mechanistic implications for CN's activity and provides a therapeutic venue for the treatment of synucleinopathies. Calcineurin (CN) is a highly conserved Ca2+–calmodulin (CaM)-dependent phosphatase that senses Ca2+ concentrations and transduces that information into cellular responses. Ca2+ homeostasis is disrupted by α-synuclein (α-syn), a small lipid binding protein whose misfolding and accumulation is a pathological hallmark of several neurodegenerative diseases. We report that α-syn, from yeast to neurons, leads to sustained highly elevated levels of cytoplasmic Ca2+, thereby activating a CaM-CN cascade that engages substrates that result in toxicity. Surprisingly, complete inhibition of CN also results in toxicity. Limiting the availability of CaM shifts CN's spectrum of substrates toward protective pathways. Modulating CN or CN's substrates with highly selective genetic and pharmacological tools (FK506) does the same. FK506 crosses the blood brain barrier, is well tolerated in humans, and is active in neurons and glia. Thus, a tunable response to CN, which has been conserved for a billion years, can be targeted to rebalance the phosphatase’s activities from toxic toward beneficial substrates. These findings have immediate therapeutic implications for synucleinopathies.