Molecular Genetics of Tau-Associated Neurodegeneration

描述（由申请人提供）：微管相关蛋白tau突变发生在一些遗传性额颞叶痴呆（FTD）病例中，表明tau异常可导致神经退行性变。许多FTD突变发生在改变剪接从而改变tau亚型表达的调控元件，而不是tau编码序列。阿尔茨海默病（AD）的标志性神经病理特征之一是神经原纤维缠结（NFT），其中含有过度磷酸化的tau蛋白。改变tau相关神经退行性过程的事件特征对于理解AD、FTD和相关疾病（如进行性核上性麻痹和皮质基底变性）的病理生理学以及治疗方法的发展至关重要。为了验证野生型tau蛋白异常表达可引起神经变性的假设，在果蝇中，人类tau蛋白最长的同型体过度表达，导致眼睛和底层大脑变性，但不能产生神经原纤维缠结。然而，通过糖原合成酶激酶(GSK)-3 β（一种重要的体外tau激酶）的果蝇同系物shaggy的共表达，tau磷酸化会产生更严重的眼睛变性，以及类似于NFT的病变（Jackson, g.r.等人，2002）：人类野生型tau与无翼通路组分相互作用，并在果蝇中产生神经原纤维病理。神经元34:509-519)。在这里，我们将研究在双tau + Shaggy转基因中，Shaggy是否被纳入nft样病变。我们将研究嘌呤霉素敏感氨基肽酶的作用，这是在一个试点筛选中确定的，作为tau修饰剂。最后，我们将进行功能丧失和功能获得遗传筛选，以确定与过度磷酸化tau表达相关的异常果蝇表型的新修饰因子。修饰基因将被表征和评估，作为开发新疗法的目标，旨在减轻阿尔茨海默病和其他神经退行性疾病的神经原纤维病理和神经元细胞死亡。

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.