Calcineurin determines toxic versus beneficial responses to α-synuclein

Proc Natl Acad Sci U S A. 2014 Aug 26;111(34):E3544-52. doi: 10.1073/pnas.1413201111. Epub 2014 Aug 13.

Abstract

Calcineurin (CN) is a highly conserved Ca(2+)-calmodulin (CaM)-dependent phosphatase that senses Ca(2+) concentrations and transduces that information into cellular responses. Ca(2+) 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 Ca(2+), 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.

Keywords: Crz1; NFAT; Slm2; TORC2; neuroinflammation.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Calcineurin / genetics
  • Calcineurin / metabolism*
  • Calcineurin Inhibitors
  • Calcium Signaling
  • Calmodulin / metabolism
  • Cells, Cultured
  • Gene Knockdown Techniques
  • Humans
  • Lewy Body Disease / metabolism
  • Mice
  • Mice, Transgenic
  • Models, Neurological
  • NFATC Transcription Factors / metabolism
  • Neurons / drug effects
  • Neurons / metabolism
  • Parkinson Disease / metabolism
  • Phosphoric Monoester Hydrolases / metabolism
  • Rats
  • Recombinant Proteins / genetics
  • Recombinant Proteins / metabolism
  • Recombinant Proteins / toxicity
  • Saccharomyces cerevisiae / drug effects
  • Saccharomyces cerevisiae / genetics
  • Saccharomyces cerevisiae / metabolism
  • Saccharomyces cerevisiae Proteins / genetics
  • Saccharomyces cerevisiae Proteins / metabolism
  • Saccharomyces cerevisiae Proteins / toxicity
  • Tacrolimus / pharmacology
  • alpha-Synuclein / genetics
  • alpha-Synuclein / metabolism*
  • alpha-Synuclein / toxicity*

Substances

  • Calcineurin Inhibitors
  • Calmodulin
  • NFATC Transcription Factors
  • NFATC4 protein, human
  • Recombinant Proteins
  • Saccharomyces cerevisiae Proteins
  • alpha-Synuclein
  • calcineurin phosphatase
  • Calcineurin
  • Phosphoric Monoester Hydrolases
  • Tacrolimus