title: Calcineurin determines toxic versus beneficial responses to α-synuclein.
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.
authors.affiliation: Whitehead Institute for Biomedical Research, Cambridge, MA 02142; Howard Hughes Medical Institute, Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139;
authors.forename: Gabriela
authors.initials: G
authors.lastname: Caraveo
authors.affiliation: Whitehead Institute for Biomedical Research, Cambridge, MA 02142; Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114; Departments of.
authors.forename: Pavan K
authors.initials: PK
authors.lastname: Auluck
authors.affiliation: Whitehead Institute for Biomedical Research, Cambridge, MA 02142;
authors.forename: Luke
authors.initials: L
authors.lastname: Whitesell
authors.affiliation: Whitehead Institute for Biomedical Research, Cambridge, MA 02142;
authors.forename: Chee Yeun
authors.initials: CY
authors.lastname: Chung
authors.affiliation: Whitehead Institute for Biomedical Research, Cambridge, MA 02142; Howard Hughes Medical Institute, Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139;
authors.forename: Valeriya
authors.initials: V
authors.lastname: Baru
authors.affiliation: Neurology and.
authors.forename: Eugene V
authors.initials: EV
authors.lastname: Mosharov
authors.affiliation: Department of Biological Sciences, The University of Alabama, Tuscaloosa, AL 35487;
authors.forename: Xiaohui
authors.initials: X
authors.lastname: Yan
authors.affiliation: Departments of Biomedical Engineering and Neuroscience, The Johns Hopkins University School of Medicine, Baltimore, MD 21205; and.
authors.forename: Manu
authors.initials: M
authors.lastname: Ben-Johny
authors.affiliation: Department of Biology, Institute of Biochemistry, Eidgenossische Technische Hochschule Zurich, Zurich CH-8093, Switzerland.
authors.forename: Martin
authors.initials: M
authors.lastname: Soste
authors.affiliation: Department of Biology, Institute of Biochemistry, Eidgenossische Technische Hochschule Zurich, Zurich CH-8093, Switzerland.
authors.forename: Paola
authors.initials: P
authors.lastname: Picotti
authors.affiliation: Department of Biological Sciences, The University of Alabama, Tuscaloosa, AL 35487;
authors.forename: Hanna
authors.initials: H
authors.lastname: Kim
authors.affiliation: Department of Biological Sciences, The University of Alabama, Tuscaloosa, AL 35487;
authors.forename: Kim A
authors.initials: KA
authors.lastname: Caldwell
authors.affiliation: Department of Biological Sciences, The University of Alabama, Tuscaloosa, AL 35487;
authors.forename: Guy A
authors.initials: GA
authors.lastname: Caldwell
authors.affiliation: Neurology and Psychiatry, Columbia University Medical Center, New York, NY 10032;
authors.forename: David
authors.initials: D
authors.lastname: Sulzer
authors.affiliation: Departments of Biomedical Engineering and Neuroscience, The Johns Hopkins University School of Medicine, Baltimore, MD 21205; and.
authors.forename: David T
authors.initials: DT
authors.lastname: Yue
authors.affiliation: Whitehead 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.
authors.forename: Susan
authors.initials: S
authors.lastname: Lindquist
mesh_terms: D000818:Animals; D019703:Calcineurin / Q000235:genetics / Q000378:metabolism*; D065095:Calcineurin Inhibitors; D020013:Calcium Signaling; D002147:Calmodulin / Q000378:metabolism; D002478:Cells, Cultured; D055785:Gene Knockdown Techniques; D006801:Humans; D020961:Lewy Body Disease / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D008959:Models, Neurological; D050778:NFATC Transcription Factors / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D010300:Parkinson Disease / Q000378:metabolism; D010744:Phosphoric Monoester Hydrolases / Q000378:metabolism; D051381:Rats; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism / Q000633:toxicity; D012441:Saccharomyces cerevisiae / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000378:metabolism / Q000633:toxicity; D016559:Tacrolimus / Q000494:pharmacology; D051844:alpha-Synuclein / Q000235:genetics / Q000378:metabolism* / Q000633:toxicity*
chemical_list: D065095:Calcineurin Inhibitors; D002147:Calmodulin; D050778:NFATC Transcription Factors; C494010:NFATC4 protein, human; D011994:Recombinant Proteins; D029701:Saccharomyces cerevisiae Proteins; D051844:alpha-Synuclein; C120817:calcineurin phosphatase; D019703:Calcineurin; D010744:Phosphoric Monoester Hydrolases; D016559:Tacrolimus
keywords: Crz1; NFAT; Slm2; TORC2; neuroinflammation