Molecular Genetics of Tau-Associated Neurodegeneration

描述（由申请人提供）：在遗传性额颞叶痴呆（FTD）的某些病例中，微管相关蛋白tau发生突变，表明tau异常可导致神经退行性变。许多FTD突变发生在调节元件中，这些元件改变了tau亚型的剪接，从而改变了tau亚型的表达，而不是tau编码序列。阿尔茨海默病（AD）的标志性神经病理学特征之一是神经元缠结（NFT），其含有过度磷酸化的tau。改变tau相关神经退行性过程的事件的表征对于理解AD以及FTD和相关疾病（如进行性核上性麻痹和皮质基底节变性）的病理生理学以及治疗药物的开发至关重要。为了检验神经变性可能由野生型tau蛋白的异常表达引起的假设，人类tau蛋白的最长同种型在果蝇中过表达，产生眼睛和底层大脑的变性，但未能产生神经元缠结。然而，通过共表达shaggy（糖原合成酶激酶（GSK）-3 β的果蝇同源物，一种重要的体外tau激酶）的tau磷酸化产生更严重的退化眼以及类似NFT的损伤（杰克逊，G.R.，等人（2002）：人类野生型tau与无翅途径组分相互作用并在果蝇中产生神经病理学。Neuron 34：509-519）。在这里，我们将研究Shaggy是否被纳入双tau + Shaggy转基因中的NFT样病变。我们将研究嘌呤霉素敏感的氨肽酶，这是在试点筛选中确定的作用，作为一个tau修饰剂。最后，我们将进行功能丧失和功能获得的遗传筛选，以确定与过度磷酸化tau蛋白表达相关的异常果蝇表型的新修饰剂。修饰基因将被表征和评价为开发新疗法的靶点，旨在减轻AD和其他神经退行性疾病中的神经病理学和神经元细胞死亡。

DESCRIPTION (provided by applicant): Mutations in the microtubule-associated protein tau occur in some cases of inherited frontotemporal dementia (FTD), demonstrating that tau abnormalities can cause neurodegeneration. Many FTD mutations occur in regulatory elements that alter splicing and thereby expression of tau isoforms, rather than tau coding sequence. One of the hallmark neuropathologic features of Alzheimer's disease (AD) is the neurofibrillary tangle (NFT), which contains hyperphosphorylated tau. Characterization of the events that modify tau-associated neurodegenerative processes is critical for understanding the pathophysiology of AD, as well as FTD and related diseases, such as progressive supranuclear palsy and corticobasal degeneration, and for the development of therapeutics. In order to test the hypothesis that neurodegeneration can be caused by aberrant expression of wild-type tau, the longest isoform of human tau was overexpressed in the fruit fly, producing degeneration of the eye and underlying brain, but failing to produce neurofibrillary tangles. However, tau phosphorylation by co-expression of shaggy, the Drosophila homologue of glycogen synthase kinase (GSK)-3beta, an important tau kinase in vitro, produced a more severely degenerated eye, as well as lesions resembling NFT (Jackson, G.R., et al. (2002): Human wild-type tau interacts with wingless pathway components and produces neurofibrillary pathology in Drosophila. Neuron 34: 509-519). Here, we will examine whether Shaggy is incorporated into NFT-like lesions in double tau + Shaggy transgenics. We will examine the role of puromycin-sensitive aminopeptidase, which was identified in a pilot screen, as a tau modifier. Finally, we will perform loss of function and gain of function genetic screens in order to identify novel modifiers of the abnormal Drosophila phenotype associated with expression of hyperphosphorylated tau. Modifier genes will be characterized and evaluated as targets for the development of new therapies aimed at alleviating neurofibrillary pathology and neuronal cell death in AD and other neurodegenerative disorders.