FKBP12 contributes to α-synuclein toxicity by regulating the calcineurin-dependent phosphoproteome.
FKBP12 contributes to α-synuclein toxicity by regulating the calcineurin-dependent phosphoproteome.
复制标题
DOI：
10.1073/pnas.1711926115
复制
发表时间：
2017-12-26
影响因子：
11.1
通讯作者：
Lindquist S
中科院分区：
文献类型：
--
作者：
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
钙调神经磷酸酶是所有真核生物中必需的钙依赖性磷酸酶。钙调神经磷酸酶是否可以内源性调节的因素以外的Ca 2+和钙调素是未知的。使用帕金森氏病（PD）作为高病理生理钙调磷酸酶活性的替代模型，并采用鸟枪蛋白质组学方法，我们表明，异构酶FKBP 12生理调节钙调磷酸酶活性，通过促进参与囊泡回收的蛋白质的去磷酸化。使用啮齿类动物模型的PD，FKBP 12和钙调磷酸酶之间的功能相互作用的部分抑制块的磷酸酶活性的关键囊泡回收蛋白质在黑质突触前末梢赋予强大的神经保护。我们的工作重新分配给FKBP 12一种新的机制，通过调节钙调磷酸酶的磷酸酶活性来支持PD模型中的毒性，具有治疗意义。钙调神经磷酸酶是一种必需的钙依赖性磷酸酶。增加的钙调磷酸酶活性与α-突触核蛋白（α-syn）毒性相关，α-syn是一种与帕金森病（PD）和其他神经退行性疾病有关的蛋白质。他克莫司可通过募集和抑制12-kDa顺-反脯氨酸异构酶FK 506结合蛋白（FKBP 12）来抑制钙调磷酸酶。钙调神经磷酸酶/FKBP 12是否代表在没有药理学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作为模型来询问在不存在他克莫司的情况下FKBP 12是否在调节钙调神经磷酸酶活性中起作用。我们发现FKBP 12深刻地影响了钙调神经磷酸酶依赖性磷酸化蛋白质组，促进了导致α-syn毒性的蛋白质亚组的去磷酸化。使用大鼠PD模型，使用低剂量的食品和药物管理局（FDA）批准的化合物他克莫司部分消除FKBP 12和钙调磷酸酶之间的功能相互作用，阻断钙调磷酸酶对这些蛋白质的活性，并保护免受α-syn病理学的毒性标志。因此，FKBP 12可以内源性调节钙调磷酸酶活性，对PD的治疗具有治疗意义。
Calcineurin is an essential Ca2+-dependent phosphatase in all eukaryotes. Whether calcineurin can be endogenously regulated by factors other than Ca2+ and calmodulin is not known. Using a model of Parkinson's Disease (PD) as a surrogate for high pathophysiological calcineurin activity and employing a shotgun proteomic approach, we show that the isomerase FKBP12 physiological regulates calcineurin activity by facilitating dephosphorylation of proteins involved in vesicle recycling. Using a rodent model of PD, partial inhibition of the functional interaction between FKBP12 and calcineurin blocks the phosphatase activity toward critical vesicle recycling proteins at nigral presynaptic terminals conferring strong neuroprotection. Our work reassigns to FKBP12 a novel mechanism that supports toxicity in a PD model by modulating calcineurin's phosphatase activity with therapeutic implications. 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.
登录
查看更多内容
影响因子：
5.6
作者：
Feyder S;De Craene JO;Bär S;Bertazzi DL;Friant S
通讯作者：
Friant S
影响因子：
64.5
作者：
LIU, J;FARMER, JD;SCHREIBER, SL
通讯作者：
SCHREIBER, SL
DOI：
10.1126/science.1245296
发表时间：
2013-11-22
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Chung CY;Khurana V;Auluck PK;Tardiff DF;Mazzulli JR;Soldner F;Baru V;Lou Y;Freyzon Y;Cho S;Mungenast AE;Muffat J;Mitalipova M;Pluth MD;Jui NT;Schüle B;Lippard SJ;Tsai LH;Krainc D;Buchwald SL;Jaenisch R;Lindquist S
通讯作者：
Lindquist S
影响因子：
15.1
作者：
Koprich, James B.;Johnston, Tom H.;Brotchie, Jonathan M.
通讯作者：
Brotchie, Jonathan M.
影响因子：
64.8
作者：
Chan, C. Savio;Guzman, Jaime N.;Surmeier, D. James
通讯作者：
Surmeier, D. James