Molecular reconstitution of cellular machinery essential for neuronal development

神经元发育所必需的细胞机器的分子重建

• 批准号: MR/J000973/1
• 负责人: Carolyn Moores
• 金额: $ 143.3万
• 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: 2012
• 资助国家: 英国
• 起止时间: 2012 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FJ000973%2F1
• 关键词: Molecular; reconstitution; cellular; machinery; essential

When you were a child, did you ever get lost amidst the towering shelves of a supermarket? That sense of something very small in a huge and complex environment is reminiscent of the challenge faced by cells of the developing brain. The adult human brain is built from billions of specialised cells called neurons. During embryonic growth, immature neurons undertake an amazing journey that involves finding their way from the centre of the developing brain, pushing past many other neurons to get to specific locations in the brain's complex structure. Successful migration enables the formation of the network of mature neurons that are essential for memory and thought. Severe human diseases including epilepsy and mental retardation, and early death, can be caused if the neurons get lost on their journey. Work in my lab is beginning to provide understanding about components of the machinery that enable neurons to navigate the complex maze of the developing brain. In the same way as our body has a skeleton, neurons have a skeleton - called the cytoskeleton - which also provides support and strength. The cytoskeleton is involved in many important aspects of the life of the cell, including cell shape and movement and it is essential for brain development. Studying the cytoskeleton is important so we can understand both how healthy cells work and malfunctions of the cytoskeleton in disease. My research team studies the three-dimensional structure of the cytoskeleton, because knowing what the cytoskeleton looks like contributes to our understanding of how it works within the cell. We use a very powerful microscope to take pictures of individual cytoskeleton molecules and then use computers to combine these pictures and calculate their three-dimensional shape. Our current research focuses on a part of the cytoskeleton called microtubules, long cylindrical structures that act as scaffolds to help neurons on the move. In this project, we will be studying a family of proteins that provide extra stability for microtubules in neurons. These proteins are called the doublecortin family of microtubule associated proteins, and they are essential for human brain development. We have had some exciting recent results from our microscope studies and we want to know more about how these proteins interact with microtubules to provide strength for migrating neurons. We also want to know how microtubule stabilisation by the doublecortin family affects the neuron's transporter motors that use microtubules as tracks to carry cargo around the cell. With this information, we hope to provide insight into how diseases of brain development occur. Our research should also provide essential clues about how immature brain cells might be used to treat brain damage later in life, for example in stroke patients or in sufferers of neurodegenerative diseases like Alzheimer's disease.

当你还是个孩子的时候，你是否曾在超市高耸的货架中迷路过？这种在巨大而复杂的环境中感受到微小事物的感觉让人想起发育中的大脑细胞所面临的挑战。成年人的大脑由数十亿个称为神经元的特殊细胞构成。在胚胎生长过程中，未成熟的神经元经历了一段奇妙的旅程，其中包括从发育中的大脑中心寻找出路，穿过许多其他神经元到达大脑复杂结构中的特定位置。成功的迁移能够形成对记忆和思维至关重要的成熟神经元网络。如果神经元在旅途中迷路，可能会导致严重的人类疾病，包括癫痫和智力低下以及过早死亡。我实验室的工作开始提供对使神经元能够在发育中的大脑的复杂迷宫中导航的机制组件的理解。就像我们的身体有骨骼一样，神经元也有一个骨骼——称为细胞骨架——它也提供支持和力量。细胞骨架涉及细胞生命的许多重要方面，包括细胞形状和运动，并且对于大脑发育至关重要。研究细胞骨架非常重要，因此我们可以了解健康细胞如何工作以及疾病中细胞骨架的功能障碍。我的研究团队研究细胞骨架的三维结构，因为了解细胞骨架的样子有助于我们了解它在细胞内的工作原理。我们使用非常强大的显微镜拍摄单个细胞骨架分子的照片，然后使用计算机将这些照片组合起来并计算它们的三维形状。我们目前的研究重点是细胞骨架的一部分，称为微管，这是一种长圆柱形结构，充当支架来帮助神经元移动。在这个项目中，我们将研究一系列为神经元微管提供额外稳定性的蛋白质。这些蛋白质被称为微管相关蛋白的双皮质素家族，它们对于人类大脑的发育至关重要。我们最近从显微镜研究中得到了一些令人兴奋的结果，我们想更多地了解这些蛋白质如何与微管相互作用，为神经元迁移提供力量。我们还想知道双皮质素家族的微管稳定性如何影响神经元的转运马达，这些转运马达使用微管作为在细胞周围运输货物的轨道。通过这些信息，我们希望能够深入了解大脑发育疾病是如何发生的。我们的研究还应该提供关于如何利用未成熟脑细胞来治疗晚年脑损伤的重要线索，例如中风患者或阿尔茨海默病等神经退行性疾病患者。

项目成果

The divergent mitotic kinesin MKLP2 exhibits atypical structure and mechanochemistry.

• DOI: 10.7554/elife.27793
• 发表时间: 2017-08-11
• 期刊: eLife
• 影响因子: 7.7
• 作者: Atherton J;Yu IM;Cook A;Muretta JM;Joseph A;Major J;Sourigues Y;Clause J;Topf M;Rosenfeld SS;Houdusse A;Moores CA
• 通讯作者: Moores CA

Conserved mechanisms of microtubule-stimulated ADP release, ATP binding, and force generation in transport kinesins.

• DOI: 10.7554/elife.03680
• 发表时间: 2014-09-10
• 期刊: eLife
• 影响因子: 7.7
• 作者: Atherton J;Farabella I;Yu IM;Rosenfeld SS;Houdusse A;Topf M;Moores CA
• 通讯作者: Moores CA

Microtubule structure by cryo-EM: snapshots of dynamic instability.

• DOI: 10.1042/ebc20180031
• 发表时间: 2018-12-07
• 期刊: Essays in biochemistry
• 影响因子: 6.4
• 作者: Manka SW;Moores CA
• 通讯作者: Moores CA

Molecular basis for specific regulation of neuronal kinesin-3 motors by doublecortin family proteins.

• DOI: 10.1016/j.molcel.2012.06.025
• 发表时间: 2012-09-14
• 期刊: MOLECULAR CELL
• 影响因子: 16
• 作者: Liu, Judy S.;Schubert, Christian R.;Fu, Xiaoqin;Fourniol, Franck J.;Jaiswal, Jyoti K.;Houdusse, Anne;Stultz, Collin M.;Moores, Carolyn A.;Walsh, Christopher A.
• 通讯作者: Walsh, Christopher A.

Systems Biochemistry and Structural Biology of Microtubule End Tracking

微管末端追踪的系统生物化学和结构生物学

• DOI: 10.1016/j.bpj.2011.11.1221
• 发表时间: 2012
• 期刊: Biophysical Journal
• 影响因子: 3.4
• 作者: Maurer S