Molecular Genetics of Tau-Associated Neurodegeneration

描述(申请人提供)：微管相关蛋白tau的突变出现在遗传性额颞叶痴呆(FTD)的一些病例中，表明tau异常可导致神经退化。许多FTD突变发生在调节元件中，这些元件改变了剪接从而改变了tau亚型的表达，而不是tau编码序列。阿尔茨海默病(AD)的标志性神经病理特征之一是神经纤维缠结(NFT)，其中含有过度磷酸化的tau。对改变tau相关神经退变过程的事件的表征对于了解AD、FTD和相关疾病(如进行性核上性瘫痪和皮质基底膜退行性变)的病理生理学以及治疗的发展至关重要。为了验证野生型tau基因异常表达可导致神经退行性变的假说，在果蝇中过表达了人类tau基因的最长亚型，导致眼睛和潜在脑的退化，但不能产生神经原纤维缠结。然而，通过共表达Shaggy，果蝇糖原合成酶激酶-3β的同源物，一种重要的tau激酶，在体外产生了更严重的退化眼睛，以及类似NFT的病变(Jackson，G.R.，等人)。(2002)：人类野生型tau与无翼途径组件相互作用，并在果蝇中产生神经原纤维病理。神经元34：509-519)。在这里，我们将检查Shaggy是否合并到双tau Shaggy转基因患者的NFT样病变中。我们将研究在中试筛选中确定的嘌呤霉素敏感氨基肽酶作为tau修饰物的作用。最后，我们将进行功能缺失和功能遗传筛选的获得，以寻找与过度磷酸化tau表达相关的果蝇异常表型的新修饰物。修饰基因将被表征和评估为新疗法的开发目标，旨在减轻AD和其他神经退行性疾病的神经纤维病理和神经细胞死亡。

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.