期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 114, 期 52, 页码 E11313-E11322出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1711926115
关键词
calcineurin; FKBP12; alpha-synuclein; Parkinson's Disease; Tacrolimus
资金
- Jeffry M. and Barbara Picower Foundation
- RJG Foundation-Judy Goldberg
- Howard Hughes Medical Institute (HHMI) Collaborative Innovation Award
- NIH Grant [5P50NS38372]
- WIBR funds for the study of regenerative biology
Calcineurin is an essential Ca2+-dependent phosphatase. Increased calcineurin activity is associated with alpha-synuclein (alpha-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 alpha-syn as a model to interrogate whether FKBP12 plays a role in regulating calcineurin activity in the absence of Tacrolimus. We showthat FKBP12 profoundly affects the calcineurin-dependent phosphoproteome, promoting the dephosphorylation of a subset of proteins that contributes to alpha-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 alpha-syn pathology. Thus, FKBP12 can endogenously regulate calcineurin activity with therapeutic implications for the treatment of PD.
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