SCREENING FOR DRUGS IN A DROSOPHILA TRANSGENIC MODEL

微管相关蛋白tau的突变发生在某些遗传性 额颞叶痴呆（FTD），表明tau异常可导致神经变性。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以由野生型tau的异常表达引起的假设，在果蝇中过表达人tau的最长同种型，产生眼睛的变性， 但无法产生神经元缠结。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，我们建议测试选定的激酶抑制剂，半胱天冬酶抑制剂和抗氧化剂的能力，以抑制双重tau +蓬松的生物测定表型。我们还将测试一个市售的FDA批准的化合物库（Microsource Discovery Systems）抑制tau +多毛果蝇外眼表型的能力。随后，我们将确定所鉴定的化合物对细胞死亡以及tau的构象和溶解度的影响。这个项目有助于加州大学洛杉矶分校的承诺， 阿尔茨海默病研究中心（ADRC），以促进研究，将导致识别 用于AD和相关病症的疾病改善疗法。该项目将与项目2互动 在转基因小鼠中评估类似化合物。

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 AIzheimer'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 propose to test selected kinase inhibitors, caspase inhibitors, and antioxidants for their ability to suppress the dual tau + shaggy bioassay phenotype. We also will test a library of commercially available, FDA-approved compounds (Microsource Discovery Systems) for their ability to suppress the external eye phenotype of tau + shaggy flies. Subsequently, we will determine the effects of identified compounds on cell death and conformation and solubility of tau. This project contributes to the commitment of the UCLA Alzheimer's Disease Research Center (ADRC) to foster research that will lead to identification of disease-modifying therapies for AD and related conditions. The Project will interact with Project 2 assessing similar compounds in transgenic mice.