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.

我们的大脑是由数十亿个称为神经元的专门细胞建造的。我们的大脑执行的许多复杂任务，包括记忆和思想，是因为神经元之间的连接使它们可以交流。在大脑发育的早期，未成熟的神经元与彼此没有连接，并且必须准确地导航到正确地集成到大脑的通信网络中。一生中健康的大脑功能取决于神经元维护良好之间的联系。如果神经元连通性和操作在任何阶段分解：在大脑发育过程中的神经元运动不准确会导致癫痫，智力残疾和早期死亡；神经元功能不完整，因为我们的大脑成熟到成年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，神经元功能的分解会引起神经退行性疾病，包括肌萎缩性侧索硬化和周围神经病。我实验室的工作正在寻求了解在发育过程中支持神经元健康的机械，并且随着我们的成熟方式，就像我们的身体具有为我们提供支持和力量的骨骼相同的方式，神经元具有骨骼 - 称为细胞骨架 - 也为它们提供了支持和力量。细胞骨架参与神经元生活的许多重要方面，并且是在成熟神经元中连通性和信号传导过程中驱动运动的机械的一部分。神经元细胞骨架的分解与发育综合征，神经退行性疾病和神经精神疾病有关。研究细胞骨架机械非常重要，因此我们可以了解健康的神经元如何操作以及机械故障如何引起疾病。该项目将重点放在一个称为微管的细胞骨架上。这些是长的圆柱结构，就像在神经元内的脚手架一样起作用，并且还充当了分子传输电动机在神经元内携带货物的轨道。特定类型的脚手架和所携带的特定类型的货物定义了神经元的功能。我们想了解该机械的构建模块是如何组合在一起的，以帮助神经元在大脑内完成许多复杂的任务。我的研究团队研究了微管的三维结构，因为知道它们的外观可以帮助我们了解它们的工作方式。我们使用称为电子显微镜的非常强大的显微镜拍摄单个微管的照片，然后使用计算机组合这些图片以计算其三维形状。利用微管机械疾病患者的信息，我们将能够找到特定机械组件的引起疾病的缺陷。将来，这些知识可能使我们能够以患病或受损的神经元的细胞骨架机械的损坏和修复细胞骨骼机械的部分。这可以减轻与痴呆，中风和身体损伤有关的症状。

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.

• 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