Whitehead Institute for Biomedical Research, Cambridge, MA 02142;
Department of Biology, Institute of Biochemistry, Eidgenössische Technische Hochschule Zurich, 8092 Zurich, Switzerland.
Proc Natl Acad Sci U S A. 2017 Dec 26;114(52):E11313-E11322. doi: 10.1073/pnas.1711926115. Epub 2017 Dec 11.
Calcineurin is an essential Ca-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 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.
钙调神经磷酸酶是一种必需的 Ca2+ 依赖性磷酸酶。钙调神经磷酸酶活性的增加与 α-突触核蛋白（α-syn）毒性有关，α-syn 是帕金森病（PD）和其他神经退行性疾病的一种蛋白。钙调神经磷酸酶可以通过 Tacrolimus 招募和抑制 12-kDa 脯氨酸异构酶 FK506 结合蛋白（FKBP12）来抑制。钙调神经磷酸酶/FKBP12 是否代表在没有药物干扰的情况下发生的天然生理相关组装仍然难以捉摸。我们利用 α-syn 作为模型，探究 FKBP12 是否在没有 Tacrolimus 的情况下在调节钙调神经磷酸酶活性中发挥作用。我们表明 FKBP12 深刻地影响钙调神经磷酸酶依赖性磷酸化组，促进了一组有助于 α-syn 毒性的蛋白质的去磷酸化。使用 PD 的大鼠模型，用低剂量的美国食品和药物管理局（FDA）批准的化合物 Tacrolimus 部分消除 FKBP12 和钙调神经磷酸酶之间的功能相互作用，可阻止钙调神经磷酸酶对这些蛋白质的活性，并防止 α-syn 病理的毒性特征。因此，FKBP12 可以内源性调节钙调神经磷酸酶活性，这对 PD 的治疗具有治疗意义。
