Molecular and Cell Biological Foundations of Proteostress-Induced Neuronal Extrusion

蛋白质应激诱导的神经元挤压的分子和细胞生物学基础

基本信息

批准号：
10753902
负责人：
MONICA A. DRISCOLL
金额：
$ 63.59万
依托单位：
RUTGERS, THE STATE UNIV OF N.J.
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-08-15 至 2028-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10753902
关键词：
Actins Actomyosin Acute Address Adult Age Alzheimer&apos s Disease Animal Model Animals Area Articulation Autophagocytosis Basic Science Biological Biology Brain Brain Diseases Caenorhabditis elegans Cardiac Myocytes Cell physiology Cells Cellular biology Collection Complex Cytokinesis Cytoskeletal Proteins Cytoskeleton Data Disease Dissection Event Foundations Future Genetic Goals Growth Hand Health Human Huntington Disease Image Individual Intervention Kinesis Knowledge Learning Lipids Longevity Measures Mediating Membrane Methods Microtubule-Organizing Center Microtubules Modeling Molecular Molecular Chaperones Molecular Genetics Movement Mus Muscle Nanotubes Nerve Degeneration Nervous System Neurodegenerative Disorders Neurons Neurosciences Organelles Organism Pathogenesis Pathology Pathway interactions Process Production Proteins Quality Control Reporting Role Route Stress System Testing Therapeutic Therapeutic Intervention Toxin Vesicle Visualization Work aging brain aging population brain health clinical development driving force extracellular genetic manipulation healthy aging human disease in vivo in vivo imaging insight mature animal multicatalytic endopeptidase complex neuronal cell body neuroprotection neurotoxic novel overexpression permissiveness polyglutamine protein aggregation protein degradation proteostasis proteotoxicity segregation tool uptake

项目摘要

Healthy aging of the brain is highly dependent upon a range of protein quality control systems, and such quality control capacity is often disrupted in neurodegenerative disease. Recently it has come to light that diseased neurons can transfer toxic products, such as aggregated proteins, to neighboring cells, likely leading to the spread of pathology within the brain. How neurons generate and send out extracellular material in vivo is a question that must be addressed as we consider therapeutic intervention. Basic research can inform on mechanisms relevant to late onset neurodegenerative disease and can suggest avenues of treatment. Our studies take advantage of the enormous technical advantages in the simple animal model C. elegans permissive of experimentation that can yield mechanistic insight into neurodegeneration and neuroprotection biology. With high conservation of molecular function and a naturally transparent body plan, lessons learned from individual neuronal dynamics directly visualized and measured within the intact adult animal provides high predictive power for understanding key subcellular processes in more complex systems, including humans. We discovered that some stressed C. elegans neurons can extrude giant vesicles we call “exophers” that can be loaded with human disease protein aggregates. Exopher formation dramatically increases upon increased challenge to protein quality control in those neurons, including over-expressing human Alzheimer’s disease fragment Aβ1-42 or Huntington’s disease-associated polyQ protein. Aggregated proteins extruded in exophers are taken up by a glial pruning-like interaction with the neighboring cell, which attempts degradation. We hypothesize that exopher production is a previously unrecognized alternative route for adult neurons to clear protein aggregates and damaged organelles. Highly similar processes of giant vesicle budding and transfer of aggregates, lipids, and damaged organelles have been recently reported in C. elegans muscle, mouse cardiomyocytes, and mouse and human brain, strongly implying that discoveries we make about how this process operates in C. elegans will be widely relevant across species, including informing on elusive spreading mechanisms operating in human brain in neurodegenerative disease. We propose to exploit the considerable advantages of the C. elegans model (transparent body, facile genetic manipulation, exquisitely defined nervous system, powerful cell biology, short lifespan) to advance fundamental understanding of exopher biology. Our goals are to define the genetic and cell biological mechanisms operative in exopher formation with a focus on the cytoskeletal roles in exophergenesis: 1) define the genetic and cell biological mechanisms of microtubule dynamics that mediate exopher formation; 2) address how a neuron accomplishes scission that releases a large aggregate-filled domain, leaving behind an intact neuron. Our work should inform on a novel pathway of proteostasis control relevant to both healthy brain aging and neurodegenerative disease, defining a new area for study and for development of clinical interventions.

大脑的健康衰老高度取决于一系列蛋白质质量控制系统和这种质量在神经退行性疾病中，控制能力通常是残疾的。最近它已经揭露了神经元可以将有毒产物（例如聚集的蛋白质）转移到相邻细胞中，可能导致大脑中病理的传播。神经元如何在体内产生和发送细胞外材料是一个我们考虑治疗干预时必须解决的问题。基础研究可以告知与晚期神经退行性疾病有关的机制，可以提出治疗途径。我们的研究利用了简单的动物模型C.秀隐杆线中的巨大技术优势。允许的实验可以产生对神经退行性和神经保护的机械洞察力生物学。具有高度保存分子功能和自然透明的身体计划，经验教训从直接在完整的成年动物中直接可视化和测量的单个神经元动力学可提供高度了解包括人类在内的更复杂系统中关键的亚细胞过程的预测能力。我们发现，一些压力强的秀丽隐杆线虫神经元可以挤出我们称为“散发器”的巨型蔬菜，可以充满人类疾病蛋白质聚集体。增长后，外异性形成大大增加这些神经元中蛋白质质量控制的挑战，包括过度表达人类阿尔茨海默氏病片段Aβ1-42或亨廷顿疾病相关的Polyq蛋白。聚集的蛋白质挤出在外通过与相邻细胞的胶质修剪样相互作用来吸收，该细胞尝试降解。我们假设外胚产生是成人神经元的先前未认可的替代途径清除蛋白质聚集体和细胞器受损。高度相似的巨型囊泡芽和最近在秀丽隐杆线虫肌肉中报道了聚集体，脂质和受损细胞器的转移，小鼠心肌细胞以及小鼠和人脑，强烈暗示我们发现我们如何该过程在秀丽隐杆线虫中运作将在各种物种中广泛相关，包括通知难以捉摸在神经退行性疾病中在人脑中运作的传播机制。我们建议利用秀丽隐杆线虫模型的可观优势（透明的身体，易于遗传操纵，精确定义神经系统，功能强大的细胞生物学，寿命短），以促进基本对外生物学的理解。我们的目标是定义遗传和细胞生物学机制在外生象形成中的手术，重点是骨骨骼中的细胞骨架作用：1）定义遗传以及介导外源形成的微管动力学的细胞生物学机制； 2）解决如何神经元完成了释放一个充满聚集体的域的细胞，留下了完整的神经元。我们的工作应该告知与健康的脑衰老和神经退行性疾病，定义了一个新的研究领域和临床干预措施的发展。