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

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

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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 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
Volume114
Issue number52
DOIs
StatePublished - Dec 26 2017

All Science Journal Classification (ASJC) codes

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    Caraveo, G., Soste, M., Cappelleti, V., Fanning, S., Van Rossum, D. B., Whitesell, L., Huang, Y., Chung, C. Y., Baru, V., Zaichick, S., Picotti, P., & Lindquist, S. (2017). FKBP12 contributes to α-synuclein toxicity by regulating the calcineurin-dependent phosphoproteome. Proceedings of the National Academy of Sciences of the United States of America, 114(52), E11313-E11322. https://doi.org/10.1073/pnas.1711926115