Biochemical and in vivo determinants of tau neurotoxicity

描述(申请人提供)：阿尔茨海默病是最常见的神经退行性疾病，病理特征是异常磷酸化和聚集的tau蛋白在神经元内沉积，并形成细胞外淀粉样斑块。Tau在神经纤维缠结中的异常沉积也是一组不太常见的疾病的主要病理特征，统称为tauopathies。为了确定控制tau诱导的神经变性的分子机制，我们(甘布林博士)对tau变体进行了广泛的生化表征，包括与家族性tau病额颞叶痴呆和与17号染色体连锁的帕金森病相关的剪接异构体和突变。重要的是，这些生化研究确定了具有改变的聚集和微管结合特性的tau变体。同时，我们(费尼博士)已经建立了果蝇的牵张症模型。我们的模型概括了人类疾病的关键特征，包括年龄依赖性神经退行性变，tau异常磷酸化，tau聚集成纤维缠绕状包裹体，以及早期死亡。我们现在将结合我们的 在生物化学和体内肌病模型方面的优势，以确定在肌病中引起细胞和组织毒性的牛磺酸的种类。

DESCRIPTION (provided by applicant): Alzheimer's disease is the most common neurodegenerative disorder and is characterized pathologically by the intraneuronal deposition of abnormally phosphorylated and aggregated tau protein and by the formation of extracellular amyloid plaques. Abnormal deposition of tau into neurofibrillary tangles is also the primary pathologic feature of a group of less common disorders, collectively termed the "tauopathies." To define the molecular mechanisms controlling tau-induced neurodegeneration we (Dr. Gamblin) have performed extensive biochemical characterization of tau variants, including splicing isoforms and mutants linked to the familial tauopathy frontotemporal dementia and parkinsonism linked to chromosome 17. Importantly, these biochemical studies have defined tau variants with altered aggregation and microtubule binding properties. In parallel we (Dr. Feany) have created Drosophila models of tauopathy. Our models recapitulate key features of the human diseases, including age-dependent neurodegeneration, abnormal tau phosphorylation, aggregation of tau into fibrillary tangle-like inclusions, and early death. We will now combine our strengths in biochemistry and in vivo tauopathy modeling to define the species of tau that cause cellular and organismal toxicity in tauopathies.