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

Research output: Contribution to journalArticle

5 Citations (Scopus)

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

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Synucleins
Tacrolimus Binding Protein 1A
Calcineurin
Tacrolimus
Parkinson Disease
cis-trans-Isomerases
Tacrolimus Binding Proteins
Peptidylprolyl Isomerase
Disease Eradication
Proteins
Poisons
United States Food and Drug Administration
Phosphoric Monoester Hydrolases
Neurodegenerative Diseases
Pharmacology
Pathology

All Science Journal Classification (ASJC) codes

  • General

Cite this

Caraveo, Gabriela ; Soste, Martin ; Cappelleti, Valentina ; Fanning, Saranna ; Van Rossum, Damian B. ; Whitesell, Luke ; Huang, Yanmei ; Chung, Chee Yeun ; Baru, Valeriya ; Zaichick, Sofia ; Picotti, Paola ; Lindquist, Susan. / FKBP12 contributes to α-synuclein toxicity by regulating the calcineurin-dependent phosphoproteome. In: Proceedings of the National Academy of Sciences of the United States of America. 2017 ; Vol. 114, No. 52. pp. E11313-E11322.
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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.",
author = "Gabriela Caraveo and Martin Soste and Valentina Cappelleti 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",
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Caraveo, G, Soste, M, Cappelleti, 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

FKBP12 contributes to α-synuclein toxicity by regulating the calcineurin-dependent phosphoproteome. / Caraveo, Gabriela; Soste, Martin; Cappelleti, Valentina; Fanning, Saranna; Van Rossum, Damian B.; Whitesell, Luke; Huang, Yanmei; Chung, Chee Yeun; Baru, Valeriya; Zaichick, Sofia; Picotti, Paola; Lindquist, Susan.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 114, No. 52, 26.12.2017, p. E11313-E11322.

Research output: Contribution to journalArticle

TY - JOUR

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

AU - Caraveo, Gabriela

AU - Soste, Martin

AU - Cappelleti, 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

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.

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U2 - 10.1073/pnas.1711926115

DO - 10.1073/pnas.1711926115

M3 - Article

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