Tau and Neurodegeneration II: A therapeutic target

由微管相关蛋白tau（tau）组成的神经元内含物是几种神经退行性疾病（包括阿尔茨海默病、进行性核上性麻痹（PSP）和皮质基底节变性（CBD））的病理学的标志性特征。tau蛋白功能障碍和神经退行性变之间的因果关系通过产生FTDP-17的tau蛋白突变的重复性来证明。当前计划的总体目标是识别影响人类神经退行性疾病中tau病理进展的修饰剂，并在此信息的基础上识别治疗靶点，这些靶点将成为最终患者治疗的基础。这一目标自然是在第一个资助期取得的进展的基础上实现的，在第一个资助期内，该计划在开发细胞培养和 Tau蛋白病的转基因动物模型以及表征这些疾病的遗传原因。这四个项目，以及一个中央神经病理学核心，构成这个计划将通过不同但互补的策略来解决这个总体目标。项目1（Farrer博士）将利用遗传学方法来鉴定增加4 R tau蛋白病（PSP和CBD）风险的tau基因变体，并确定这些变体导致疾病的机制。因此，该项目将确定这些疾病的潜在治疗靶点。项目2（Yen博士）将利用早期tau蛋白丝形成和发病机制的细胞培养模型来研究几种被认为是tau蛋白病原因的因素（例如氧化应激，蛋白酶体抑制）的影响。该项目将在该细胞模型中鉴定tau发病机制的修饰剂，然后可以在我们的转基因模型中进行研究。项目3个 （赫顿）和4（达夫）将采用该计划在过去4年中开发的tau蛋白病转基因小鼠模型，研究初步研究已经确定的潜在靶点。项目3将研究分子伴侣Hsp 70及其共分子伴侣CHIP对tau发病机制的影响，而项目4将研究tau磷酸化对病理学和神经变性的影响。

Neurofibrillary inclusions composed of the microtubule associated protein tau (tau) are a hallmark feature ot the pathology in several neurodegenerative diseases including Alzheimer's disease, Progressive supranuclear Palsy (PSP) and Corticobasal Degeneration (CBD). A causal link between tau dysfunction and neurodegeneration was demonstrated by the idenification of mutations in tau that give rise to FTDP-17. The overall goal of this current program is to identify modifiers that influence the progression of tau pathology, in human neurodegenerative disease and to build on this information to identify therapeutic targets that will form the basis for eventual patient treatments. This goal follows on naturally from the progress made in the first period of funding in which this Program was highly successful in developing both cell culture and transgenic animal models of tauopathy as well as in characterizing the genetic causes of these diseases. The four projects, alongwith a central Neuropathology core, that make up this program will address this overall goal through different but complementary strategies. Project 1 (Dr Farrer) will utilize a genetic approach to identify tau gene variants that increase the risk for developing 4R tauopathy (PSP and CBD) and will determine the mechanism by which these variants lead to disease. This project will thus define a potential therapeutic target in these diseases. Project 2 (Dr Yen) will utilize a cell culture model of early stage tau filament formation and pathogenesis to study the impact of several factors that have been suggested as causes of tauopathy (eg oxidative stress, proteasome inhibition). This project will identify modifiers of tau pathogenesis in this cell model that can then be studied in our transgenic models. Projects 3 (Hutton) and 4 (Duff) will employ transgenic mouse models of tauopathy developed by the Program over the past 4 years to study potential targets already identified by preliminary studies. Project 3 will study the impact of the chaperone Hsp70 and its co-chaperone CHIP on tau pathogenesis whilst Project 4, will examine the impact of tau phosphorylation on pathology and neurodegeneration.