Department of Pharmacology and Experimental Therapeutics, Boston University School of Medicine, Boston, MA 02118, USA.
German Center for Neurodegenerative Diseases (DZNE), Von-Siebold-Str. 3a, 37075 Göttingen, Germany.
Sci Adv. 2023 Feb 3;9(5):eadd9789. doi: 10.1126/sciadv.add9789. Epub 2023 Feb 1.
Alzheimer's disease and related tauopathies are characterized by the pathogenic misfolding and aggregation of the microtubule-associated protein tau. Understanding how endogenous chaperones modulate tau misfolding could guide future therapies. Here, we show that the immunophilin FKBP12, the 12-kDa FK506-binding protein (also known as FKBP prolyl isomerase 1A), regulates the neuronal resilience by chaperoning a specific structure in monomeric tau. Using a combination of mouse and cell experiments, in vitro aggregation experiments, nuclear magnetic resonance-based structural analysis of monomeric tau, site-specific phosphorylation and mutation, as well as structure-based analysis using the neural network-based structure prediction program AlphaFold, we define the molecular factors that govern the binding of FKBP12 to tau and its influence on tau-induced neurotoxicity. We further demonstrate that tyrosine phosphorylation of tau blocks the binding of FKBP12 to two highly specific structural motifs in tau. Our data together with previous results demonstrating FKBP12/tau colocalization in neurons and neurofibrillary tangles support a critical role of FKBP12 in regulating tau pathology.
阿尔茨海默病和相关的 tau 病的特征是微管相关蛋白 tau 的致病性错误折叠和聚集。了解内源性伴侣蛋白如何调节 tau 的错误折叠，可以指导未来的治疗方法。在这里，我们表明免疫亲和素 FKBP12（也称为 FKBP 脯氨酰异构酶 1A 的 12kDa FK506 结合蛋白）通过伴侣单体 tau 中的特定结构来调节神经元的弹性。我们使用小鼠和细胞实验、体外聚集实验、基于核磁共振的单体 tau 结构分析、定点磷酸化和突变、以及使用基于神经网络的结构预测程序 AlphaFold 的结构分析，定义了控制 FKBP12 与 tau 结合及其对 tau 诱导的神经毒性影响的分子因素。我们进一步证明 tau 的酪氨酸磷酸化阻止了 FKBP12 与 tau 中两个高度特异性结构基序的结合。我们的数据以及先前证明神经元和神经原纤维缠结中 FKBP12/tau 共定位的结果支持 FKBP12 在调节 tau 病理学中的关键作用。
