Format

Send to

Choose Destination
See comment in PubMed Commons below
Proc Natl Acad Sci U S A. 2014 Aug 26;111(34):E3544-52. doi: 10.1073/pnas.1413201111. Epub 2014 Aug 13.

Calcineurin determines toxic versus beneficial responses to α-synuclein.

Author information

  • 1Whitehead Institute for Biomedical Research, Cambridge, MA 02142; Howard Hughes Medical Institute, Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139;
  • 2Whitehead Institute for Biomedical Research, Cambridge, MA 02142; Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114; Departments of.
  • 3Whitehead Institute for Biomedical Research, Cambridge, MA 02142;
  • 4Neurology and.
  • 5Department of Biological Sciences, The University of Alabama, Tuscaloosa, AL 35487;
  • 6Departments of Biomedical Engineering and Neuroscience, The Johns Hopkins University School of Medicine, Baltimore, MD 21205; and.
  • 7Department of Biology, Institute of Biochemistry, Eidgenossische Technische Hochschule Zurich, Zurich CH-8093, Switzerland.
  • 8Neurology and Psychiatry, Columbia University Medical Center, New York, NY 10032;
  • 9Whitehead Institute for Biomedical Research, Cambridge, MA 02142; Howard Hughes Medical Institute, Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139; lindquist@wi.mit.edu.

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

PMID:
25122673
PMCID:
PMC4151770
DOI:
10.1073/pnas.1413201111
[PubMed - indexed for MEDLINE]
Free PMC Article
PubMed Commons home

PubMed Commons

0 comments
How to join PubMed Commons

    Supplemental Content

    Full text links

    Icon for HighWire Icon for PubMed Central
    Loading ...
    Support Center