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

• Published in: Proceedings of the National Academy of Sciences - PNAS 2017-12, Vol.114 (52), p.E11313-E11322
• Main Authors: 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
• Format: Article
• Language: English
• Subjects: alpha-Synuclein - genetics; alpha-Synuclein - metabolism; Animals; Biological Sciences; Calcineurin - genetics; Calcineurin - metabolism; Disease Models, Animal; Parkinson Disease - drug therapy; Parkinson Disease - genetics; Parkinson Disease - metabolism; Parkinson Disease - pathology; Phosphoproteins - genetics; Phosphoproteins - metabolism; PNAS Plus; Proteome - genetics; Proteome - metabolism; Rats; Rats, Sprague-Dawley; Tacrolimus - pharmacology; Tacrolimus Binding Protein 1A - genetics; Tacrolimus Binding Protein 1A - metabolism
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1711926115

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 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.