FKBP12 contributes to α-synuclein toxicity by regulating the calcineurin-dependent phosphoproteome

Gabriela Caraveo, Martin Soste, Valentina Cappelletti, Saranna Fanning, Damian B. Van Rossum, Luke Whitesell, Yanmei Huang, Chee Yeun Chung, Valeriya Baru, Sofia Zaichick, Paola Picotti, Susan Lindquist

Research output: Contribution to journalArticlepeer-review

28 Scopus citations


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 showthat FKBP12 profoundly affects the calcineurindependent 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.

Original languageEnglish (US)
Pages (from-to)E11313-E11322
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number52
StatePublished - Dec 26 2017

All Science Journal Classification (ASJC) codes

  • General


Dive into the research topics of 'FKBP12 contributes to α-synuclein toxicity by regulating the calcineurin-dependent phosphoproteome'. Together they form a unique fingerprint.

Cite this