The Propyl Isomerase Pin 1 and Neurodegeneration

描述（由申请人提供）： 阿尔茨海默病 (AD) 及相关疾病的一个神经病理学标志是神经原纤维缠结，其主要成分是过度磷酸化的 tau（一种微管结合蛋白）。 AD 中缠结的形成先于 tau 蛋白和其他蛋白质在脯氨酸之前的某些丝氨酸或苏氨酸残基 (pSer/Thr-Pro) 上的磷酸化增加而发生。尽管磷酸化可以消除 tau 结合微管并促进其组装的能力，但人们对磷酸化的实际作用以及它如何影响 tau 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，其转化通常受到磷酸化的抑制，但会受到脯氨酰异构酶 Pin1 的特异性催化。 Pin1活性可以在体外直接或通过促进其去磷酸化间接恢复磷酸化tau的微管功能。值得注意的是，人类 AD 大脑中的可溶性 Pin1 已被耗尽。重要的是，我们的初步结果表明，Pin1 表达的亚区域水平与正常大脑中神经变性的预测脆弱性呈负相关，也与 AD 大脑中的早期神经原纤维变性呈负相关。此外，我们的初步结果还表明，小鼠中 Pin1 的缺失会导致磷酸化 tau 和 tau 丝的渐进性年龄依赖性积累以及神经元变性和损失。因此，Pin1 是第一个缺失导致年龄依赖性神经变性和 tau 蛋白病的基因，Pin1 介导的磷酸化后调节机制可能在神经变性的发展中发挥关键作用。在本提案中，我们将首先使用小鼠模型，通过将 Pin1 缺失或过度表达的小鼠与其他具有 tan 相关表型的转基因小鼠杂交，确定 Pin1 如何影响 tau 蛋白病表型的发展。其次，我们将使用培养细胞模型系统来确定 Pin1 如何调节 tau 功能并影响 tau 相关表型的发展，并检查 Pin1 在 Aβ 诱导的神经毒性中的作用。最后，我们将研究 Pin1 功能在人类 tau蛋白病的发展过程中是否以及如何失调。这些研究应该有助于阐明 AD 和相关疾病的分子机制，并且也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.