Spatial and temporal mechanisms controlling diverse myosin motor functions in health and disease

我们的老龄人口中有很大一部分受到迟发性神经退行性疾病的影响，如运动神经元病或阿尔茨海默病。更好地了解导致这些神经退行性疾病的原因将导致新的治疗和预防策略。我们的研究集中在小的纳米级分子马达蛋白上，这些蛋白质可以驱动货物沿着轨道到达细胞内的特定位置，就像火车沿着铁路网行驶到特定的目的地一样。在我们之前的研究中发现的特殊接头蛋白的帮助下，货物被连接到马达上。了解这些分子机器是如何被控制和调节的是很重要的，因为这些肌球蛋白马达的缺陷会导致不同形式的痴呆。我们研究的第一个目标是研究一种新的开/关开关，我们认为这种开关可能会触发马达开始向细胞内的目的地移动。此外，我们将确定特定的货物分子是如何附着在马达上的，以及在旅程结束时，货物是如何与马达分离的。在第二个项目中，我们将分析MYO6的特定功能，MYO6是一种不寻常的带倒挡装置的肌球蛋白马达，以及它在星形胶质细胞中的一种转运蛋白，星形胶质细胞是大脑中一种特殊类型的胶质细胞。神经胶质细胞在大脑中有许多功能；它们保护和支持神经细胞，并通过一种称为吞噬作用的过程清除大脑中的死细胞。我们将确定MYO6的缺失是否会导致清除大脑碎片的缺陷。在第三个项目中，我们将研究为什么在阿尔茨海默氏症中，大脑中被称为小胶质细胞的特定免疫细胞有更多的另一种叫做MYO1F的肌球蛋白。在这些患者中，小胶质细胞变得“过度活跃”，大脑开始发炎。我们将研究MYO1F的增加是否会导致大脑的炎症，以及我们是否可以通过关闭这种肌球蛋白来抑制炎症。肌凝蛋白马达是可药物治疗的靶点，已有几种抑制剂可用于不同类型的肌凝蛋白。因此，我们相信我们的研究将开辟新的领域，将指导未来的临床研究和潜在的诊断工具和可能的治疗策略的发展。

A significant proportion of our ageing population is affected by the late onset of neurodegenerative disorders such as motor neuron or Alzheimer's disease. A better understanding of what causes these neurodegenerative diseases will lead to new therapeutic and preventive strategies. Our research is focused on small nanoscale molecular motor proteins that drive cargo along tracks to specific sites in the cell, rather like a train running along a railway network to its specific destinations. The cargo is hooked up to this motor with the help of specific adaptor proteins that we have previously identified in our research. It is important to understand how these molecular machines are controlled and regulated, since defects in these myosin motors can cause different forms of dementia. The first aim of our research is to investigate a new on/off switch that we believe may trigger the motor to start moving to its destinations in the cell. Furthermore, we will determine how the specific cargo molecules are attached to the motor and how the cargo is uncoupled from the motor at the end of the journey. In a second project we will analyse the specific function of MYO6, an unusual myosin motor with a reverse gear, and one of its cargo adaptor proteins in astrocytes, which are a specific type of glia cell in the brain. Glia cells have many functions in the brain; they protect and support nerve cells and clear the brain of dead cells by a process called phagocytosis. We will determine whether the absence of MYO6 causes defects in clearance of debris from the brain.In a third project we will investigate why, in Alzheimer's disease, specific immune cells in the brain called microglia have more of another myosin, called MYO1F. In these patients, the microglia become 'hyperactive' and the brain becomes inflamed. We will investigate whether increased MYO1F contributes to the inflammation of the brain, and whether we can inhibit the inflammation by turning off this myosin. Myosin motors are druggable targets and a few inhibitors are already available for different classes of myosins. Thus we believe that our research will open up new areas that will guide future clinical studies and the development of potential diagnostic tools and possible therapeutic strategies.