Building blocks of molecular complexity: the neuronal 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，包括记忆和思考，都是因为神经元之间建立联系，使它们能够交流。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：大脑发育过程中神经元运动不准确会导致癫痫、智力残疾和过早死亡；当我们的大脑成熟到成年时，神经元功能的不完全维持会导致神经精神疾病，包括精神分裂症和情绪障碍；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，包括肌萎缩性侧索硬化症和周围神经病变。我实验室的工作是试图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。细胞骨架参与神经元生命的许多重要方面，是成熟神经元发育和维持连接和信号传导过程中驱动运动的机制的一部分。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。特定类型的支架和特定类型的负载决定了神经元的功能。我们想了解这个机器的组成部分是如何组合在一起，以帮助神经元在大脑中完成许多复杂的任务的。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。我们使用一种叫做电子显微镜的非常强大的显微镜来拍摄单个微管的照片，然后用计算机将这些照片组合起来计算它们的三维形状。利用来自微管机械疾病患者的信息，我们将能够定位特定机械部件的致病缺陷。在未来，这些知识可能使我们能够靶向和修复病变或受损神经元中细胞骨架机制的损坏部分。这可以减轻与痴呆、中风和身体损伤相关的症状。

Our brains are built from billions of specialised cells called neurons. The many complex tasks that our brains perform, including memory and thought, 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 epilepsy, intellectual disability and early death; incomplete maintenance of neuronal function as our brains mature into adulthood can cause neuropsychiatric illnesses including schizophrenia and mood disorders; and breakdown of neuronal function as we age can cause neurodegenerative disorders including amyotrophic lateral sclerosis and peripheral neuropathies. 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 movement during development and maintenance of connectivity and signaling in mature neurons. Breakdown of the neuronal cytoskeleton is associated with developmental syndromes, neurodegenerative diseases and neuropsychiatric illness. 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 particular type of scaffolding and the particular type of cargo that is carried defines how the neuron functions. We would like to understand how the building blocks of this machinery are put together 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 and then use computers to combine these pictures to calculate their three-dimensional shape. Using information from patients with diseases of the microtubule machinery, we will be able to locate disease-causing defects to particular machinery components.In the future, this knowledge may allow us to target and repair the broken parts of the cytoskeleton machinery in diseased or damaged neurons. This could allow alleviation of symptoms associated with dementia, stroke and physical injury.