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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.

大脑的健康老化高度依赖于一系列蛋白质质量控制系统，并且这种质量控制系统可以使大脑健康老化。在神经变性疾病中，控制能力经常被破坏。最近人们发现，神经元可以将有毒产物，如聚集的蛋白质，转移到邻近的细胞，可能导致神经元的死亡。病理学在大脑中的传播。神经元如何在体内产生和发出细胞外物质是一个重要的问题。这是我们在考虑治疗干预时必须解决的问题。基础研究可以提供与迟发性神经退行性疾病相关的机制，并可以提出治疗途径。我们的研究利用了简单动物模型C的巨大技术优势。elegans 允许实验，可以产生对神经变性和神经保护的机械见解生物学由于分子功能的高度保守性和自然透明的身体结构，从在完整的成年动物内直接可视化和测量的单个神经元动力学，具有理解更复杂系统（包括人类）中关键亚细胞过程的预测能力。我们发现有些人强调C。线虫的神经元可以挤出我们称之为“外泌体”的巨大囊泡，装载人类疾病蛋白质聚集体。出窍者的形成在增加时显著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病片段Aβ1-42或亨廷顿病相关polyQ蛋白。聚集的蛋白质在胞外体中挤出通过与邻近细胞的类似神经胶质修剪的相互作用而被吸收，这试图降解。我们假设exopher的产生是一种以前未被认识到的成年神经元的替代途径，清除蛋白质聚集体和受损的细胞器。巨大的泡状体出芽过程和最近在C.线虫肌肉，小鼠心肌细胞，以及小鼠和人类大脑，这强烈暗示着我们关于如何该过程在C中操作。秀丽线虫将在物种之间广泛相关，包括提供难以捉摸的信息。在神经退行性疾病中在人脑中运作的传播机制。我们建议充分利用C. elegans模型（透明体，易遗传操纵，精细定义的神经系统，强大的细胞生物学，短寿命），以推进基础了解外泌体生物学我们的目标是确定遗传和细胞生物学机制在外泌体形成中起作用，重点是外泌体发生中的细胞骨架作用：1）定义遗传以及介导外泌体形成的微管动力学的细胞生物学机制; 2）解决神经元完成分裂，释放出一个大的聚集体填充的结构域，留下一个完整的神经元。我们的工作应该告知一个新的途径蛋白质稳态控制相关的健康的大脑老化，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。