Calcineurin determines toxic versus beneficial responses to α-synuclein

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*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

58 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)E3544-E3552
JournalProceedings of the National Academy of Sciences of the United States of America
Volume111
Issue number34
DOIs
StatePublished - Aug 26 2014

Keywords

  • Crz1
  • NFAT
  • Neuroinflammation
  • Slm2
  • TORC2

ASJC Scopus subject areas

  • General

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