Regulation and resilience of the neuronal microtubule cytoskeleton in health and disease

我们的大脑是由数十亿个被称为神经元的特殊细胞组成的。我们大脑执行的许多复杂任务，包括思考和记忆，都是因为神经元之间建立了联系，使它们能够进行交流。在大脑发育的早期，未成熟的神经元彼此之间没有连接，必须精确地定位到正确的位置，才能正确地整合到大脑的通信网络中。在我们的一生中，健康的大脑功能依赖于我们神经元之间的连接得到良好的维护。如果神经元连接和操作在任何阶段中断，都可能发生严重的人类疾病。在大脑发育过程中，不准确的神经元运动可能导致智力残疾、癫痫和早逝。当我们的大脑成熟到成年时，神经元功能的不完全维持也会导致包括精神分裂症在内的神经精神疾病。随着年龄的增长，神经元功能的崩溃会导致神经退行性疾病，如肌萎缩性侧索硬化症（ALS）。在所有这些疾病的情况下，还有很多东西需要学习，我的实验室正在努力了解在发育和成熟过程中支持神经元健康的机制。就像我们的身体有一个骨架为我们提供支持和力量一样，神经元也有一个骨架——叫做细胞骨架——它也给它们提供支持和力量。细胞骨架参与了神经元生命的许多重要方面，是驱动神经元在发育过程中运动的机制的一部分，同时也维持了成熟神经元的连通性和通信。神经细胞骨架的破坏与发育综合征、神经退行性疾病和神经精神疾病有关。研究细胞骨架机制很重要，这样我们就可以了解健康的神经元是如何运作的，以及机制故障是如何导致疾病的。这个项目将关注细胞骨架的一部分，称为微管。这些是长圆柱形结构，在神经元内部起到脚手架的作用，同时也是分子运输马达在神经元内运送货物的轨道。微管机器的组织和稳定性，以及它所携带的特定类型的货物，决定了神经元的功能。我们想了解神经元微管是如何组装和维护的，以帮助神经元在大脑中承担许多复杂的任务。我的研究小组研究微管的三维结构，因为知道它们的样子可以帮助我们理解它们是如何工作的。我们使用一种非常强大的显微镜，称为电子显微镜，来拍摄单个微管的照片，这些微管要么是在试管中组装的，要么是在活神经元中形成的。然后，我们用计算机将这些电子显微镜图片结合起来，计算出微管的三维形状。通过使用来自扰乱微管机制的疾病患者的信息，我们将能够将致病缺陷映射到特定的机制组件上。在未来，从我们的工作中获得的知识可能使我们能够瞄准并修复病变或受损神经元中细胞骨架机制的损坏部分。这样的理解也可能为痴呆症、中风和身体损伤的新疗法提供启示。

Our brains are built from billions of specialised cells called neurons. The many complex tasks that our brains perform, including thought and memory, occur because neurons make connections with each other that allow them to communicate. Early in brain development, immature neurons are not connected to each other and must navigate to exactly the right position to correctly integrate into the brain's communication network. Healthy brain function throughout our lives depends on the connections between our neurons being well maintained. Severe human diseases can occur if neuron connectivity and operation breaks down at any stage. Inaccurate neuron movement during brain development can cause intellectual disability, epilepsy and early death. Incomplete maintenance of neuronal function as our brains mature into adulthood can also cause neuropsychiatric illnesses including schizophrenia. Breakdown of neuronal function as we age can cause neurodegenerative disorders such as amyotrophic lateral sclerosis (ALS). In all these disease scenarios, there remains much to learn, and work in my lab is seeking to understand the machinery that supports neuronal health during development and as we mature.In the same way as our body has a skeleton that provides us with support and strength, neurons have a skeleton - called the cytoskeleton - which also gives them support and strength. The cytoskeleton is involved in many important aspects of neuronal life, and is part of the machinery that drives neuron movement during development, along with maintenance of connectivity and communication in mature neurons. Breakdown or disruption of the neuronal cytoskeleton is associated with developmental syndromes, neurodegenerative diseases and neuropsychiatric illnesses. Studying the cytoskeleton machinery is important so we can understand both how healthy neurons operate and how machinery malfunction causes disease.This project will focus on a part of the cytoskeleton called microtubules. These are long cylindrical structures that act like scaffolding inside the neuron and also act as tracks along which molecular transport motors carry cargo within the neuron. The organisation and stability of the microtubule machinery, together with the particular type of cargo that is carried along it, defines how the neuron functions. We would like to understand how the neuronal microtubules are assembled and maintained to help neurons undertake their many complex tasks within the brain. My research team studies the three-dimensional structure of microtubules, because knowing what they look like can help us understand how they work. We use a very powerful microscope called an electron microscope to take pictures of individual microtubules that have either been assembled in a test tube or form within a living neuron. We then use computers to combine these electron microscope pictures to calculate the microtubules' three-dimensional shape. By using information from patients with diseases that disrupt the microtubule machinery, we will be able to map disease-causing defects to particular machinery components.In the future, knowledge arising from our work may allow us to target and repair the broken parts of the cytoskeleton machinery in diseased or damaged neurons. Such understanding could also shed light on new treatments for dementia, stroke and physical injury.