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

从途径到目标：利用超灵敏光学成像阐明神经退行性变的分子机制

• 批准号: MR/V023861/1
• 负责人: Suman De
• 金额: $ 144.29万
• 依托单位: University of Sheffield
• 依托单位国家: 英国
• 项目类别: Fellowship
• 财政年份: 2022
• 资助国家: 英国
• 起止时间: 2022 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FV023861%2F1
• 关键词: pathways; targets; Untangling; molecular; mechanisms

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.

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。有超过75万人患有这些毁灭性的疾病生活在英国，在未来30年，患病率估计将增加到200多万。如果痴呆症的发病时间推迟五年，到2050年，患有这些疾病的人将减少85万。然而，目前还没有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，否则这些破坏性疾病的负担可能会使我们的社会和卫生服务不堪重负。大多数神经退行性疾病都有一个共同的标志性特征，即疾病特异性蛋白质在中枢神经系统中的不适当沉积。例如，阿尔茨海默氏病通常以两种不同的蛋白质-淀粉样蛋白-β和tau -在神经细胞中或周围沉积为特征。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。这些正常功能的蛋白质或肽在一定条件下在神经细胞内或周围相互粘附，形成各种团块。这些团块，基于它们的物理和化学特征，可以以特定的方式通过中枢神经系统的相互连接的区域传播，导致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，以及它们中哪些是最有害的。作为谢菲尔德大学转化神经科学研究所的UKRI未来领袖研究员，我的目标将是开发一个可靠的模型和灵敏的方法来研究疾病相关蛋白质的聚集和传播。我将集中讨论一组称为tau蛋白病的疾病，其特征是一种称为tau的特定蛋白质的沉积。我将使用tau蛋白病患者的皮肤细胞，并重新编程它们，使其在培养皿中形成不同类型的神经细胞。这些重新编程的神经细胞将重演疾病的开始和传播，其方式与人类大脑中发生的类似。然后，我将开发超灵敏的显微镜方法，以可视化这种患者源性神经细胞模型系统中的个体致病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，这些物种如何通过细胞系统的连接网络传播，哪些类型的tau物种对神经细胞的损害最大，以及它们如何损害神经细胞以促进疾病进展。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，皮质基底节变性，并确定为什么这些疾病表现出不同的临床症状，疾病进展的可变速率和不同的发病年龄。我将在这些疾病的模型中确定tau聚集和传播途径的共性和差异，这将有助于区分具有不同tau蛋白病的患者，并且可能对于成功诊断至关重要，特别是在疾病的早期阶段，以及允许开发减轻tau蛋白的策略-开发可靠的方法来检测和监测相关模型系统中的个体tau蛋白将加速我们对tau聚集和扩散的机械理解，因为它发生在人脑中，反过来，将提供加速新治疗方法所需的关键见解。