Assessing the Role of Tau in Synaptic Architecture and Function

由于我们生活在人口老龄化中，认知、感觉和运动能力下降以及阿尔茨海默病（AD）和额颞叶痴呆（FTD）等神经退行性疾病的患病率正在上升。突触是一种特殊的细胞连接，它包含复杂的机制，允许信号在神经元之间传递。在衰老和神经退行性疾病期间，突触机制被破坏。这会导致神经网络的变化，随后是认知、感觉和运动能力的下降。然而，这些突触机制变化的潜在原因尚不清楚。为了帮助回答这个问题，该项目将研究Tau蛋白在调节突触中的新作用。Tau蛋白在包括AD和某些形式的FTD在内的许多神经退行性疾病的发展中起着关键作用。这些疾病，被称为Tau病，是由Tau突变或蛋白质本身的失调引起的。除了Tau蛋白在神经退行性疾病中的作用外，Tau蛋白的错误定位和聚集也是大脑老化的标志。综上所述，Tau可能是开发与年龄相关的认知能力下降、AD和FTD治疗的理想治疗靶点。考虑到Tau蛋白在痴呆发病机制中的作用及其治疗潜力，了解其生理功能至关重要。已知Tau丢失通过触发微管和轴突运输畸变，影响突触的形成和维持，导致小鼠和果蝇中与年龄相关的突触缺陷。最近一项来自实验室的蛋白质组学研究发现，Tau蛋白与一系列复杂的因子结合，这些因子在调节突触功能方面很重要。我的项目将通过研究Tau蛋白与蛋白质组学研究中发现的新型相互作用蛋白的关系来研究Tau蛋白在突触结构中的作用。该项目将使用果蝇作为其遗传适应性、强大的实验策略和强大的行为分析的模式生物。

As we are living in an ageing population, the prevalence of cognitive, sensory and motor decline, as well as neurodegenerative diseases such as Alzheimer's disease (AD) and Fronto-Temporal Dementia (FTD), is increasing.Synapses are specialised cell junctions which contain complex machinery to allow the transmission of signals from neuron to neuron. During ageing and neurodegenerative disease, the synaptic machinery is disrupted. This leads to changes in neuronal networks, followed by cognitive, sensory and motor decline. However, the underlying causes of these changes to synaptic machinery are not well understood. To help answer this question, the project will study novel roles of Tau in regulating synapses. Tau is a protein which plays a key role in the development of many neurodegenerative disorders including AD and some forms of FTD. These disorders, known as the Tauopathies, arise from mutations in Tau or the dysregulation of the protein itself. Besides Tau's role in neurodegenerative disease, Tau mis-localisation and aggregation are also hallmarks of the ageing brain. Taken together, Tau could be an ideal therapeutic target for the development of treatments of age-related cognitive decline, AD and FTD.Considering Tau's roles in the pathogenesis of dementia and its potential as treatment, understanding its physiological function is vital. Tau loss has been known to lead to age-related synaptic deficits in mice and the fruit fly Drosophila by triggering microtubule and axonal transport aberrations, affecting synapse formation and maintenance. A recent proteomics study from the lab identified that Tau binds to a complex array of factors that are important in regulating synaptic function. My project will be studying the roles of Tau in synaptic architecture by investigating its relation to novel interacting proteins identified in the proteomics study. The project will be using Drosophila as the model organism for its genetic amenability, powerful experimental strategies and robust behavioural assays.