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dc.contributor.author
Caraveo, Gabriela
dc.contributor.author
Soste, Martin
dc.contributor.author
Cappelleti, Valentina
dc.contributor.author
Fanning, Saranna
dc.contributor.author
Van Rossum, Damian B.
dc.contributor.author
Whitesell, Luke
dc.contributor.author
Huang, Yanmei
dc.contributor.author
Chung, Chee Y.
dc.contributor.author
Baru, Valeriya
dc.contributor.author
Zaichick, Sofia
dc.contributor.author
Picotti, Paola
dc.contributor.author
Lindquist, Susan
dc.date.accessioned
2018-01-16T13:48:17Z
dc.date.available
2018-01-08T03:42:39Z
dc.date.available
2018-01-16T13:48:17Z
dc.date.issued
2017-12-26
dc.identifier.issn
0027-8424
dc.identifier.issn
1091-6490
dc.identifier.other
10.1073/pnas.1711926115
en_US
dc.identifier.uri
http://hdl.handle.net/20.500.11850/226166
dc.identifier.doi
10.3929/ethz-b-000226166
dc.description.abstract
Calcineurin is an essential Ca2+-dependent phosphatase. Increased calcineurin activity is associated with α-synuclein (α-syn) toxicity, a protein implicated in Parkinson’s Disease (PD) and other neurodegenerative diseases. Calcineurin can be inhibited with Tacrolimus through the recruitment and inhibition of the 12-kDa cis-trans proline isomerase FK506-binding protein (FKBP12). Whether calcineurin/FKBP12 represents a native physiologically relevant assembly that occurs in the absence of pharmacological perturbation has remained elusive. We leveraged α-syn as a model to interrogate whether FKBP12 plays a role in regulating calcineurin activity in the absence of Tacrolimus. We show that FKBP12 profoundly affects the calcineurin-dependent phosphoproteome, promoting the dephosphorylation of a subset of proteins that contributes to α-syn toxicity. Using a rat model of PD, partial elimination of the functional interaction between FKBP12 and calcineurin, with low doses of the Food and Drug Administration (FDA)-approved compound Tacrolimus, blocks calcineurin’s activity toward those proteins and protects against the toxic hallmarks of α-syn pathology. Thus, FKBP12 can endogenously regulate calcineurin activity with therapeutic implications for the treatment of PD.
en_US
dc.format
application/pdf
dc.language.iso
en
en_US
dc.publisher
National Academy of Sciences
en_US
dc.rights.uri
http://creativecommons.org/licenses/by-nc-nd/4.0/
dc.subject
Calcineurin
en_US
dc.subject
FKBP12
en_US
dc.subject
α -synuclein
en_US
dc.subject
Parkinson’s Disease
en_US
dc.subject
Tacrolimus
en_US
dc.title
FKBP12 contributes to α-synuclein toxicity by regulating the calcineurin-dependent phosphoproteome
en_US
dc.type
Journal Article
dc.rights.license
Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International
dc.date.published
2017-12-11
ethz.journal.title
Proceedings of the National Academy of Sciences of the United States of America
ethz.journal.volume
114
en_US
ethz.journal.issue
52
en_US
ethz.journal.abbreviated
Proc Natl Acad Sci U S A
ethz.pages.start
E11313
en_US
ethz.pages.end
E11322
en_US
ethz.version.deposit
publishedVersion
en_US
ethz.identifier.scopus
ethz.publication.place
Washington, DC
en_US
ethz.publication.status
published
en_US
ethz.leitzahl
ETH Zürich::00002 - ETH Zürich::00012 - Lehre und Forschung::00007 - Departemente::02030 - Dep. Biologie / Dep. of Biology::02538 - Institut für Molekulare Systembiologie / Institute for Molecular Systems Biology::03927 - Picotti, Paola / Picotti, Paola
en_US
ethz.leitzahl.certified
ETH Zürich::00002 - ETH Zürich::00012 - Lehre und Forschung::00007 - Departemente::02030 - Dep. Biologie / Dep. of Biology::02538 - Institut für Molekulare Systembiologie / Institute for Molecular Systems Biology::03927 - Picotti, Paola / Picotti, Paola
ethz.date.deposited
2018-01-08T03:42:41Z
ethz.source
SCOPUS
ethz.eth
yes
en_US
ethz.availability
Open access
en_US
ethz.rosetta.installDate
2018-01-16T13:48:23Z
ethz.rosetta.lastUpdated
2022-03-28T18:54:03Z
ethz.rosetta.versionExported
true
ethz.COinS
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