Understanding the Exopher: A Novel Mechanism for Extrusion of Neurotoxic Content

描述（由申请人提供）：大脑的健康衰老需要对蛋白质合成/降解系统以及持续的细胞器功能进行细致的维护。最近，人们开始认识到神经元可以产生可以被邻近细胞吸收的产物——有人推测，这种机制可能与疾病在大脑内的传播有关。神经元如何在体内产生和吸收大尺寸的细胞外物质是一个悬而未决的问题。我们在简单的动物模型秀丽隐杆线虫中研究衰老的神经系统，其中单个神经元，以及它们内部的聚集体和线粒体，可以很容易地在活细胞中可视化。我们意外地发现，一些秀丽隐杆线虫的神经元可以分泌出大量的细胞质（“胞外胞体”）。这些被大量排出的包裹的内容可能包含引入的人类疾病蛋白聚集体或线粒体。初步数据表明，它们可以被周围的细胞吸收。我们假设我们已经确定了一种新的替代途径，成年神经元清除蛋白质聚集体和有缺陷的细胞器。我们推测，这种机制以及周围细胞释放和摄取的相关机制在物种中是保守的，并且与目前未知的人类大脑中与疾病相关的机制有关，并在衰老过程中被破坏。我们建议利用秀丽隐杆线虫模型系统的相当大的优势（透明的身体，易于遗传操作，精细定义的神经系统，强大的细胞生物学，寿命短），以显着推进对外星生物学的理解。我们的目标是了解外显子产生的机制和增加其产量的因素；为了测试外胚芽的产生是否对产生外胚芽的神经元有益；明确外生体生产与老化的关系；并探索外胚芽转移到邻近细胞的机制和后果。我们的工作应该记录一个与健康的大脑老化和广泛的神经退行性疾病相关的细胞维持的新途径，为研究和治疗干预的发展定义一个新的领域。

DESCRIPTION (provided by applicant): Healthy aging of the brain requires meticulous maintenance of protein synthesis/degradation systems as well as sustained organelle function. Recently it has come to be appreciated that neurons can produce products that can be taken up by neighboring cells-there is speculation that this mechanism might be involved in disease spread within the brain. How neurons generate and take up large-sized extracellular material in vivo is an open question. We study the aging nervous system in the simple animal model C. elegans, in which individual neurons, as well as aggregates and mitochondria within them, can easily be visualized in the living cell. We have unexpectedly discovered that some C. elegans neurons can exude large packets of cytoplasm ("exophers"). The contents of these dramatically expelled packets can contain introduced human disease protein aggregates or mitochondria. Preliminary data suggest they can be taken up by surrounding cells. We hypothesize that we have identified a novel alternative route for adult neurons to clear protein aggregates and defective organelles. We speculate that this mechanism, and the associated mechanism of release and uptake by surrounding cells, is conserved across species and related to currently unknown mechanisms operating in human brain relevant to disease and disrupted in aging. We propose to exploit the considerable advantages of the C. elegans model system (transparent body, easy genetic manipulation, exquisitely defined nervous system, powerful cell biology, short lifespan) to markedly advance understanding of exopher biology. Our goals are to understand the mechanisms by which exophers are generated and the factors that increase their production; to test whether exopher production is beneficial to the neuron that makes it; to define the relationship of exopher production to aging; and to probe mechanisms, and consequences of, exopher transfer to neighboring cells. Our work should document a novel pathway of cell maintenance relevant to both healthy brain aging and a wide spectrum of neurodegenerative diseases, defining a new area for study and for development of therapeutic interventions.