Building blocks of molecular complexity: the neuronal cytoskeleton in health and disease

分子复杂性的组成部分：健康和疾病中的神经元细胞骨架

• 批准号: MR/R000352/1
• 负责人: Carolyn Moores
• 金额: $ 172.36万
• 依托单位: Birkbeck, University of London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2017
• 资助国家: 英国
• 起止时间: 2017 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FR000352%2F1
• 关键词: Building; blocks; molecular; complexity; neuronal

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.

我们的大脑由数十亿个称为神经元的特殊细胞组成。我们的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了连接，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，必须导航到正确的位置才能正确地融入大脑的通信网络。在我们的一生中，健康的大脑功能取决于我们的神经元之间的连接得到良好的维护。如果神经元连接和运作在任何阶段发生故障，可能会发生严重的人类疾病：大脑发育期间神经元运动不准确可能导致癫痫、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可能导致神经精神疾病，包括精神分裂症和情绪障碍;随着年龄的增长，神经元功能的破坏可引起神经变性疾病，包括肌萎缩性侧索硬化和周围神经病。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为我们提供支持和力量的骨架一样，神经元也有一个骨架-称为细胞骨架-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，并且是在成熟神经元中的连接和信号传导的发育和维持期间驱动运动的机制的一部分。神经元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。研究细胞骨架机制是很重要的，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。本项目将集中在细胞骨架的一部分，称为微管。这些长圆柱形结构就像神经元内的脚手架，也像分子运输马达在神经元内运送货物的沿着的轨道。特定类型的支架和携带的特定类型的货物决定了神经元的功能。我们想了解这种机制的构建块是如何组合在一起的，以帮助神经元在大脑中承担许多复杂的任务。我的研究团队研究微管的三维结构，因为知道它们的样子可以帮助我们了解它们是如何工作的。我们使用一种非常强大的电子显微镜来拍摄单个微管的照片，然后用计算机将这些照片联合收割机组合起来，计算出它们的三维形状。利用来自微管机器疾病患者的信息，我们将能够定位特定机器组件的致病缺陷。在未来，这些知识可能使我们能够靶向和修复患病或受损神经元中细胞骨架机器的损坏部分。这可以减轻与痴呆症，中风和身体损伤相关的症状。

项目成果

A structural model for microtubule minus-end recognition and protection by CAMSAP proteins.

• DOI: 10.1038/nsmb.3483
• 发表时间: 2017-11
• 期刊: Nature structural & molecular biology
• 影响因子: 16.8
• 作者: Atherton J;Jiang K;Stangier MM;Luo Y;Hua S;Houben K;van Hooff JJE;Joseph AP;Scarabelli G;Grant BJ;Roberts AJ;Topf M;Steinmetz MO;Baldus M;Moores CA;Akhmanova A
• 通讯作者: Akhmanova A

Molecular mechanism of a parasite kinesin motor and implications for its inhibition

寄生虫驱动蛋白运动的分子机制及其抑制的意义

• DOI: 10.1101/2021.01.26.428220
• 发表时间: 2021
• 作者: Cook A

Mitotic phosphorylation by NEK6 and NEK7 reduces the microtubule affinity of EML4 to promote chromosome congression

• DOI: 10.1126/scisignal.aaw2939
• 发表时间: 2019-08-13
• 期刊: SCIENCE SIGNALING
• 影响因子: 7.3
• 作者: Adib, Rozita;Montgomery, Jessica M.;Fry, Andrew M.
• 通讯作者: Fry, Andrew M.

Visualising the cytoskeletal machinery in neuronal growth cones using cryo-electron tomography

使用冷冻电子断层扫描可视化神经元生长锥中的细胞骨架机制

• DOI: 10.1101/2021.08.06.455451
• 发表时间: 2021
• 作者: Atherton J

The mechanism of kinesin inhibition by kinesin-binding protein.

驱动蛋白结合蛋白抑制运动蛋白的机制。

• DOI: 10.7554/elife.61481
• 发表时间: 2020-11-30
• 期刊: eLife
• 影响因子: 7.7
• 作者: Atherton J;Hummel JJ;Olieric N;Locke J;Peña A;Rosenfeld SS;Steinmetz MO;Hoogenraad CC;Moores CA
• 通讯作者: Moores CA