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

doi:10.1073/pnas.1711926115

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

^*Corresponding author for this work

Neurology

Research output: Contribution to journal › Article › peer-review

29 Scopus citations

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 language	English (US)
Pages (from-to)	E11313-E11322
Journal	Proceedings of the National Academy of Sciences of the United States of America
Volume	114
Issue number	52
DOIs	https://doi.org/10.1073/pnas.1711926115
State	Published - Dec 26 2017

Funding

ACKNOWLEDGMENTS. We thank James Surmeier, Dimitri Krainc, Jeffrey N. Savas, and Linda Clayton for valuable comments; Amanda Del Rosario for all her help with the iTRAQ spectrometry work at the Biopolymer and Proteomics Facility at the Massachusetts Institute of Technology; George W. Bell at the Whitehead Institute for all of his initial help analyzing the shotgun MS data; and Kaitlyn Mary McGrath for her help with illustrations. This work was supported by funds from the Jeffry M. and Barbara Picower Foundation, funds from the RJG Foundation–Judy Goldberg, a Howard Hughes Medical Institute (HHMI) Collaborative Innovation Award, NIH Grant 5P50NS38372, WIBR funds for the study of regenerative biology, and a gift from Ofer Nemirovsky. S.L. was an HHMI Investigator.

Keywords

Calcineurin
FKBP12
Parkinson's Disease
Tacrolimus
α-synuclein

ASJC Scopus subject areas

General

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10.1073/pnas.1711926115

Cite this

Caraveo, G., Soste, M., Cappelletti, 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

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title = "FKBP12 contributes to α-synuclein toxicity by regulating the calcineurin-dependent phosphoproteome",

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.",

keywords = "Calcineurin, FKBP12, Parkinson's Disease, Tacrolimus, α-synuclein",

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

note = "Funding Information: ACKNOWLEDGMENTS. We thank James Surmeier, Dimitri Krainc, Jeffrey N. Savas, and Linda Clayton for valuable comments; Amanda Del Rosario for all her help with the iTRAQ spectrometry work at the Biopolymer and Proteomics Facility at the Massachusetts Institute of Technology; George W. Bell at the Whitehead Institute for all of his initial help analyzing the shotgun MS data; and Kaitlyn Mary McGrath for her help with illustrations. This work was supported by funds from the Jeffry M. and Barbara Picower Foundation, funds from the RJG Foundation–Judy Goldberg, a Howard Hughes Medical Institute (HHMI) Collaborative Innovation Award, NIH Grant 5P50NS38372, WIBR funds for the study of regenerative biology, and a gift from Ofer Nemirovsky. S.L. was an HHMI Investigator.",

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Caraveo, G, Soste, M, Cappelletti, V, Fanning, S, Van Rossum, DB, Whitesell, L, Huang, Y, Chung, CY, 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, vol. 114, no. 52, pp. E11313-E11322. https://doi.org/10.1073/pnas.1711926115

TY - JOUR

T1 - FKBP12 contributes to α-synuclein toxicity by regulating the calcineurin-dependent phosphoproteome

AU - Caraveo, Gabriela

AU - Soste, Martin

AU - Cappelletti, Valentina

AU - Fanning, Saranna

AU - Van Rossum, Damian B.

AU - Whitesell, Luke

AU - Huang, Yanmei

AU - Chung, Chee Yeun

AU - Baru, Valeriya

AU - Zaichick, Sofia

AU - Picotti, Paola

AU - Lindquist, Susan

N1 - Funding Information: ACKNOWLEDGMENTS. We thank James Surmeier, Dimitri Krainc, Jeffrey N. Savas, and Linda Clayton for valuable comments; Amanda Del Rosario for all her help with the iTRAQ spectrometry work at the Biopolymer and Proteomics Facility at the Massachusetts Institute of Technology; George W. Bell at the Whitehead Institute for all of his initial help analyzing the shotgun MS data; and Kaitlyn Mary McGrath for her help with illustrations. This work was supported by funds from the Jeffry M. and Barbara Picower Foundation, funds from the RJG Foundation–Judy Goldberg, a Howard Hughes Medical Institute (HHMI) Collaborative Innovation Award, NIH Grant 5P50NS38372, WIBR funds for the study of regenerative biology, and a gift from Ofer Nemirovsky. S.L. was an HHMI Investigator.

PY - 2017/12/26

Y1 - 2017/12/26

N2 - 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.

AB - 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.

KW - Calcineurin

KW - FKBP12

KW - Parkinson's Disease

KW - Tacrolimus

KW - α-synuclein

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

Abstract

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Keywords

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