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

描述（由申请人提供）：大脑的健康老化需要蛋白质合成/降解系统的精心维护以及持续的细胞器功能。最近，人们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大脑内的疾病传播有关。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。我们用简单的动物模型C.在线虫中，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C。线虫神经元可以渗出大的细胞质包（“外泌体”）。这些显著排出的包的内容物可以包含引入的人类疾病蛋白质聚集体或线粒体。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，以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间是保守的，并且与人类大脑中目前未知的与疾病相关的机制有关，并在衰老中被破坏。我们建议充分利用C. elegans模型系统（透明的身体，易于遗传操作，精致的神经系统，强大的细胞生物学，短寿命），以显着推进对exopher生物学的理解。我们的目标是了解外泌体产生的机制和增加其产生的因素;测试外泌体的产生是否对产生它的神经元有益;定义外泌体产生与衰老的关系;并探索外泌体转移到邻近细胞的机制和后果。我们的工作应该记录一种与健康的大脑衰老和广泛的神经退行性疾病相关的细胞维持的新途径，为研究和开发治疗干预措施定义一个新的领域。

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.