FKBP12 contributes to α-synuclein toxicity by regulating the calcineurin-dependent phosphoproteome
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Van Rossum, Damian B.
Chung, Chee Y.
- Journal Article
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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 show that FKBP12 profoundly affects the calcineurin-dependent 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 Show more
Journal / seriesProceedings of the National Academy of Sciences of the United States of America: PNAS
Pages / Article No.
PublisherNational Academy of Sciences
SubjectCalcineurin; FKBP12; α -synuclein; Parkinson’s Disease; Tacrolimus
Organisational unit03927 - Picotti, Paola / Picotti, Paola
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