The Propyl Isomerase Pin 1 and Neurodegeneration

描述（由申请人提供）： 阿尔茨海默病（AD）和相关疾病的神经病理学标志是神经元缠结，其主要成分是过度磷酸化的tau，一种微管结合蛋白。AD中缠结的形成已经显示在脯氨酸之前的某些丝氨酸或苏氨酸残基（pSer/Thr-Pro）上的tau和其他蛋白质的磷酸化增加之前。虽然磷酸化可以消除tau蛋白结合微管并促进其组装的能力，但人们对磷酸化实际上做了什么以及它如何影响tau蛋白病的发病机制知之甚少。有趣的是，蛋白质中的pSer/Thr-Pro基序以不同的顺式和反式构象存在，其转化通常被磷酸化抑制，但被脯氨酰异构酶Pin 1特异性催化。Pin 1活性可以直接或间接地通过促进磷酸化tau蛋白的去磷酸化来恢复其微管功能。值得注意的是，可溶性Pin 1在人类AD脑中被耗尽。重要的是，我们的初步结果表明，Pin 1表达的次区域水平与预测的正常脑神经变性的脆弱性呈负相关，也与AD脑的早期神经退行性变。此外，我们的初步结果还表明，小鼠中Pin 1的缺失导致磷酸化tau和tau丝的进行性年龄依赖性积累以及神经元变性和丢失。因此，Pin 1是第一个缺失导致年龄依赖性神经退行性变和tau蛋白病的基因，Pin 1介导的磷酸化后调节机制可能在神经退行性变的发生发展中起关键作用。在这项提案中，我们将首先确定Pin 1如何影响tau蛋白病表型的发展，使用小鼠模型，通过杂交Pin 1无效或过表达小鼠与其他可用的转基因小鼠，具有tan相关表型。其次，我们将使用培养的细胞模型系统来确定Pin 1如何调节tau功能并影响tau相关表型的发展，并研究Pin 1在A β诱导的神经毒性中的作用。最后，我们将研究Pin 1功能是否以及如何在人类tau蛋白病的发展过程中被解除管制。这些研究有助于阐明AD及相关疾病的分子机制，并可能对其治疗产生新的影响。

DESCRIPTION (provided by applicant): A neuropathological hallmark in Alzheimer disease (AD) and related disorders is the neurofibrillary tangles, whose main component is hyperphosphorylated tau, a microtubule-binding protein. The formation of the tangles in AD has been shown to be preceded by increased phosphorylation of tau and other proteins on certain serine or threonine residues preceding proline (pSer/Thr-Pro). Although phosphorylation can abolish the ability of tau to bind microtubules and to promote their assembly, little is known about what phosphorylation actually does and how it affects the pathogenesis of the tauopathies. Interestingly, pSer/Thr- Pro motifs in proteins exist in distinct cis and trans conformations, whose conversion is normally inhibited by phosphorylation, but is specifically catalyzed by the prolyl isomerase Pin1. Pin1 activity can restore the microtubule function of phosphorylated tau directly or indirectly via promoting its dephosphorylation in vitro. Significantly, soluble Pin1 is depleted in human AD brains. Importantly, our preliminary results show that the subregional levels of Pin1 expression inversely correlate with the predicted vulnerability to neurodegeneration in normal brain, and also with early neurofibrillary degeneration in AD brain. Furthermore, our preliminary results also show that deletion of Pin1 in mice causes progressive age dependent accumulation of phosphorylated tau and tau filaments as well as neuronal degeneration and loss. Thus, Pin1 is the first gene whose deletion causes age-dependent neurodegeneration and tauopathy and Pin1 mediated post-phosphorylation regulatory mechanism may play a critical role in the development of neurodegeneration. In this proposal, we will first determine how Pin1 affects the development of the tauopathy phenotypes using mouse models by crossbreeding Pin1 null or overexpressing mice with other available transgenic mice that have tan-related phenotypes. Second, we will use cultured cell model systems to determine how Pin1 regulates tau function and affects the development of tau-related phenotypes and to examine the role of Pin1 in ABeta-induced neurotoxicity. Finally, we will investigate whether and how Pin1 function is deregulated during the development of human tauopathies. These studies should help elucidate the molecular mechanisms of AD and related disorders, and may also have novel implications for their therapies.