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The myosin VI interactome: the role of motor cargo/adaptor complexes and ubiquitin-binding during selective autophagy

肌球蛋白 VI 相互作用组：运动货物/适配器复合物和泛素结合在选择性自噬过程中的作用

基本信息

批准号：
MR/K000888/1
负责人：
Folma Buss
金额：
$ 63.95万
依托单位：
University of Cambridge
依托单位国家：
英国
项目类别：
Research Grant
财政年份：
2013
资助国家：
英国
起止时间：
2013 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=MR%2FK000888%2F1
关键词：
myosin VI interactome role motor

项目摘要

A significant proportion of our ageing population is affected by the late onset of neurodegenerative disorders such as Alzheimer's, motor neuron or Parkinson's diseases. A better understanding of what causes these neurodegenerative diseases could lead to new therapeutic and preventive strategies or could at least improve the quality of life of the affected patients. More and more research now suggests that motor neuron disease and some forms of dementia are linked to defects in a cellular pathway that is used to digest abnormal proteins or defective parts of the cell. These defects can lead to an accumulation of these protein as large clumps, which may clog up the transport of essential cargo along nerves in our limbs and eventually cause the nerve cells to die. Our research is focused on the special molecular motor protein myosin VI, which drives cargo along tracks in the opposite direction to all other motors to specific sites in the cell, rather like a train running along a railway network to its specific destinations. The cargo is hooked up to the motor with the help of specific adaptor proteins that we have identified in our research. New results now show that this motor protein is present on protein lumps found in nerve cells from patients that died from Alzheimer's disease. Furthermore, it was recently shown that mistakes (mutations) in the protein optineurin, which links myosin VI to specific cargos, causes an inherited form of motor neuron disease. We will thus explore whether myosin VI and optineurin move and dispose of these toxic protein lumps and prevent their accumulation to avoid the death of nerve cells and subsequent neurodegenerative diseases.We thus hope to identify the precise roles of myosin VI and its adaptor proteins in the pathway that is important for clearance of protein aggregates to keep the nerve cells healthy. This will open up new areas of research that may guide future clinical studies and the development of potential diagnostic tools and possible therapeutic strategies.

老年人口中有很大一部分受到迟发性神经退行性疾病的影响，如阿尔茨海默病、运动神经元病或帕金森病。更好地了解导致这些神经退行性疾病的原因可能会导致新的治疗和预防策略，或者至少可以改善受影响患者的生活质量。现在越来越多的研究表明，运动神经元疾病和某些形式的痴呆与细胞通路的缺陷有关，细胞通路用于消化异常蛋白质或细胞的缺陷部分。这些缺陷会导致这些蛋白质聚集成大团块，这可能会阻碍我们四肢神经上重要货物的运输，最终导致神经细胞死亡。我们的研究重点是一种特殊的分子运动蛋白myosin VI，它可以沿着与所有其他马达相反的方向将货物沿着轨道运送到细胞内的特定位置，就像火车沿着铁路网行驶到特定的目的地一样。在我们研究中发现的特殊接头蛋白的帮助下，货物被连接到马达上。新的研究结果表明，这种运动蛋白存在于死于阿尔茨海默病的患者的神经细胞中发现的蛋白质块上。此外，最近的研究表明，将肌凝蛋白VI与特定货物连接起来的optinineurin蛋白的错误（突变）会导致遗传性运动神经元疾病。因此，我们将探讨肌球蛋白VI和视神经蛋白是否移动和处理这些有毒蛋白块，并防止它们的积累，以避免神经细胞死亡和随后的神经退行性疾病。因此，我们希望确定肌凝蛋白VI及其接头蛋白在清除蛋白质聚集体以保持神经细胞健康的重要途径中的确切作用。这将开辟新的研究领域，可能指导未来的临床研究和潜在诊断工具和可能的治疗策略的发展。

项目成果

期刊论文数量（10）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

MYO6 is targeted by $\textit{Salmonella}$ virulence effectors to trigger PI3-kinase signaling and pathogen invasion into host cells

MYO6 被 $ extit{沙门氏菌}$ 毒力效应子靶向，触发 PI3 激酶信号传导和病原体入侵宿主细胞

DOI：
10.17863/cam.9636
发表时间：
2017
期刊：
影响因子：
0
作者：
Brooks A
通讯作者：
Brooks A

MYO6 is targeted by Salmonella virulence effectors to trigger PI3-kinase signaling and pathogen invasion into host cells

DOI：
10.1073/pnas.1616418114
发表时间：
2017-04-11
期刊：
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
影响因子：
11.1
作者：
Brooks, Andrew B. E.;Humphreys, Daniel;Koronakis, Vassilis
通讯作者：
Koronakis, Vassilis

Myosin VI maintains the actin-dependent organization of the tubulobulbar complexes required for endocytosis during mouse spermiogenesis

肌球蛋白 VI 维持小鼠精子发生过程中内吞作用所需的肌动蛋白依赖性管球复合体组织