The role of astrocytes in early pathogenesis of motor neuron disease: a mechanistic study of neuronal degeneration and synaptic alterations

运动神经元病(MND)是一种迅速致残的疾病，导致全身肌肉无力，最终死亡，最常见的是呼吸肌瘫痪。在三年的中位生存时间内，患者的生活质量显着下降，不仅是因为身体残疾，而且还因为不同程度的痴呆症。在英国，每300-500人中就有1人面临患上这种疾病的风险，任何时候都会有大约5000人受到影响。这是无法治愈的，迫切需要开发成功的治疗方法。为了实现这一点，我们需要了解神经细胞中发生的问题，也就是神经元及其周围环境中发生的问题。导致残疾的直接问题是运动神经元，这是一种特殊的神经细胞，通常传递电脉冲来实现肌肉收缩。然而，MND研究中的一项重大突破发现，参与支持神经元功能的神经胶质细胞也可以患病。星形胶质细胞是一种与运动神经元密切相互作用的胶质细胞，已被证明直接损害或破坏它们之间的重要串扰，导致肌肉无力。这些机制通常发生在MND中，为新的治疗提供了一个合乎逻辑的靶点。在过去的十年里，作为一名研究人员和执业神经学家，我的工作是基于理解星形胶质细胞和神经元之间的对话。我们在剑桥大学成立了一个研究小组，进行了基本的观察，支持了星形胶质细胞默认用于修复受损运动神经元的观点。现在，我还组织了创新的合作，以发展我的技能集，并使用与人类疾病相关的最新模型来识别星形胶质细胞和运动神经元关系中的问题所在。这项工作的最终目的是获得能够帮助我们治疗(甚至可能治愈)MND的洞察力。

Motor neuron disease (MND) is a rapidly disabling condition, leading to generalized muscle weakness and finally to death most commonly by paralysis of breathing muscles. The patients' quality of life is significantly reduced during the median survival time of three years not only by physical disabilities but also by dementia to a variable degree. In the UK 1 in 300-500 people are at risk of developing this disease, affecting about 5000 people at any time. It is untreatable and there is urgent need to develop successful therapies. In order to achieve this we need to understand the problems occurring in nerve cells, called neurons and also in their surroundings.The immediate issue causing disability is within motor neurons, specialized nerve cells that normally convey electrical impulses to achieve muscle contraction. However, a major breakthrough in MND research identified that glial cells involved in supporting the function of neurons can be diseased too. Astrocytes, a type of glial cell that closely interact with motor neurons, have been shown to directly harm or to disrupt important cross-talk between them, resulting in muscle weakness. These mechanisms commonly occur in MND, providing a logical target for new treatments.Over the last decade as a researcher and practicing neurologist, my work was based on understanding the dialogue between astrocytes and neurons. Establishing a research group at the University of Cambridge, we have made fundamental observations supporting the idea that by default astrocytes are meant to repair damaged motor neurons. Now, I also assembled innovative collaborations to develop my skill-set and to use state-of-art models relevant to human disease to identify what goes wrong in the astrocyte and motor neuron relationship. The ultimate aim of this work is to gain insight that can help us to treat (and even possibly cure) MND.