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精心维护蛋白质合成/降解系统以及持续的细胞器功能。最近，人们开始意识到，神经元可以产生可以被邻近细胞吸收的产物--有猜测认为，这种机制可能参与了疾病在大脑中的传播。神经元在体内如何产生和吸收大量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线虫中研究了老化的神经系统，在这个模型中，单个神经元以及其中的聚集体和线粒体很容易在活细胞中被可视化。我们出人意料地发现，线虫的一些神经元可以分泌大包的细胞质(“外显”)。这些被戏剧性地排出的包中的内容可能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成年神经元清除蛋白质聚集体和有缺陷的细胞器的一种新的替代途径。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不同物种之间是保守的，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。我们建议利用线虫模型系统的巨大优势(透明的身体，容易的遗传操作，精确的神经系统，强大的细胞生物学，短的寿命)来显著提高对外植体生物学的理解。我们的目标是了解胞外物质产生的机制和增加其产量的因素；测试胞外物质的产生是否有利于制造它的神经元；确定胞外物质的产生与衰老的关系；以及探索胞外物质转移到邻近细胞的机制和后果。我们的工作应该记录一条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.