From pathways to targets: Untangling the molecular mechanisms of neurodegeneration using ultra-sensitive optical imaging

神经退行性疾病，如阿尔茨海默病（AD）、帕金森病（PD）和运动神经元病（MND）的患病率在现代老龄化社会中迅速上升。在英国，有超过75万人患有这些毁灭性的疾病，在未来30年里，患病率估计将增加到200多万。如果痴呆症的发病推迟5年，到2050年将减少85万人患有这些疾病。然而，目前还没有一种治疗方法可以在这些情况下保护神经元或减缓疾病进展。除非找到有效的治疗或预防方法，否则这些毁灭性疾病的负担可能会压倒我们的社会和卫生服务。大多数神经退行性疾病都有一个标志性特征，即中枢神经系统中疾病特异性蛋白的不适当沉积。例如，阿尔茨海默病的常见特征是两种不同的蛋白质——淀粉样蛋白和tau蛋白——在神经细胞内或周围沉积。相比之下，α -突触核蛋白和TDP-43蛋白的沉积分别是帕金森病和运动神经元疾病的标志性特征。在一定条件下，这些正常功能的蛋白质或肽在神经细胞内部或周围相互粘在一起，形成各种各样的团块。根据它们的物理和化学特征，这些团块可以以一种特定的方式扩散到中枢神经系统的相互连接的区域，造成神经细胞的损伤或死亡。然而，我们并不完全了解这些团块最初是如何形成的，它们在疾病进展过程中是如何传播的，以及其中哪些是最有害的。作为谢菲尔德大学转化神经科学研究所UKRI未来领导者研究员，我的目标是开发一种可靠的模型和敏感的方法来研究疾病相关蛋白的聚集和繁殖。我将重点介绍一组叫做tau病的疾病，其特征是一种叫做tau的特定蛋白质的沉积。我会用牛头病患者的皮肤细胞在培养皿中重新编程，制造不同类型的神经细胞。这些重新编程的神经细胞将以类似于人类大脑的方式重现疾病的开始和传播。然后，我将开发超灵敏显微镜方法，在这种患者来源的神经细胞模型系统中可视化单个致病的tau聚集体。我将确定与疾病相关的tau物种最初是如何形成的，这些物种是如何通过细胞系统的连接网络传播的，哪些类型的tau物种对神经细胞最具破坏性以及它们如何破坏神经细胞从而导致疾病进展。我将比较tau蛋白在各种tau诱导的神经退行性疾病中的作用，如阿尔茨海默病、皮克病、进行性核上性麻痹、皮质基底变性，并确定为什么这些疾病表现出不同的临床症状、不同的疾病进展率和不同的发病年龄。我将确定这些疾病模型中tau聚集和传播途径的共性和异同，这将有助于区分不同的tau病患者，并可能对成功诊断至关重要，特别是在疾病的早期阶段，以及允许开发减轻tau蛋白诱导的神经元损伤的策略。开发可靠的方法来检测和监测相关模型系统中的单个tau蛋白，将加速我们对tau聚集和传播的机制理解，因为它发生在人类大脑中，反过来，将提供加速新治疗方法所需的关键见解。

The prevalence of neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), and motor neuron disease (MND) is rising rapidly in modern ageing societies. There are more than 750,000 people with these devastating disorders living in the UK, and over the next 30 years, the prevalence is estimated to increase to more than 2 million. If the onset of dementia is delayed by five years, 850 thousand fewer people will be living with these diseases by 2050. However, currently, no treatment exists that can protect neurons in these conditions or slow disease progression. Unless effective treatments, or preventions are found, the burden of these devastating disorders threatens to overwhelm our social and health services.Most neurodegenerative diseases share a hallmark feature which is the inappropriate deposition of disease-specific protein(s) in the central nervous system. For example, Alzheimer's disease is commonly characterised by the deposition of two different proteins - amyloid-beta and tau - in or around the nerve cells. In contrast, deposition of alpha-synuclein and TDP-43 protein are the hallmark features of Parkinson's disease and motor neuron disease, respectively. These normally functioning proteins or peptides stick to each other, under certain conditions, within or around nerve cells to form a variety of clumps. These clumps, based on their physical and chemical features, can spread through interconnected regions of the central nervous system in a specific manner causing injury or death to the nerve cells. However, we do not entirely understand how these clumps initially form, how they spread during disease progression and which of them are the most harmful.As a UKRI Future Leader Fellow at the University of Sheffield Institute for Translational Neuroscience, my goal will be to develop a reliable model and sensitive methods to study the aggregation and propagation of disease-relevant proteins. I will focus on a group of disease called tauopathies, which are characterised by the deposition of a specific protein called tau. I will use skin cells from tauopathy patients and reprogram them to make different types of nerve cells in a dish. These reprogrammed nerve cells will recapitulate the start and spread of disease in a similar manner as happens in the human brain. Then I will develop ultrasensitive microscopy methods to visualise individual disease-causing tau aggregates in this patient-derived nerve cell model system. I will determine how disease-relevant tau species initially form, how these species spread through the connected network of the cellular system, which types of tau species are most damaging to the nerve cells and how they damage the nerve cells to contribute to disease progression. I will compare the role of tau protein in various tau-induced neurodegenerative diseases such as Alzheimer's disease, Pick's disease, Progressive Supranuclear Palsy, Corticobasal Degeneration, and determine why these diseases show different clinical symptoms, variable rates of disease progression and different ages of disease onset. I will determine the commonalities and dissimilarities of tau aggregation and propagation pathways in models of these diseases, which will help to discriminate between the patients with distinct tauopathies and might be essential for successful diagnostics, especially at the early stages of the disease, as well as allowing the development of strategies to mitigate tau protein-induced neuronal damage.Developing reliable methods to detect and monitor individual tau proteins in relevant model systems will accelerate our mechanistic understanding of tau aggregation and spread as it happens in the human brain which, in turn, will provide the critical insights needed to accelerate new therapeutic approaches.