Defining Roles of Genetics and Age in Extrusion of Neurotoxic Aggregates

阿尔茨海默病正在肆虐世界老年人口，并造成健康和社会问题。 负担似乎会增加。基础研究可以为与以下方面有关的机制提供信息： 迟发性神经变性疾病和建议治疗途径。健康老龄化 大脑需要精心维护蛋白质合成/折叠/降解系统， 这种能力在神经变性疾病中经常被破坏。最近， 认识到疾病神经元可以产生有毒产物，如聚集的蛋白质， 被邻近的细胞吸收-有猜测认为这种机制可能 与大脑内的疾病传播有关。神经元如何产生和发出大尺寸的 细胞外物质在体内是一个悬而未决的问题， 治疗干预 我们用简单的动物模型C. elegans，in which哪一个individual个体 在活体动物中，可以容易地观察到神经元以及其中的标记聚集体。 我们意外地发现，一些C。线虫的神经元可以分泌出大的包， 叫“外客”这些戏剧性地驱逐exophers的内容可以包含介绍 人类疾病蛋白质聚集体。夸大蛋白质折叠的多种方法 这些神经元中的压力，包括过度表达人类阿尔茨海默病相关的 片段A β 1 -42，以及遗传或免疫缺陷蛋白分支 体内平衡，增加外泌体形成。在胞外体中挤出的聚集蛋白质可以是 被远处的细胞吸收 我们假设，我们已经确定了一个以前未被认识的替代途径，成人 神经元清除蛋白质聚集体。我们推测，这种机制，以及相关的 释放和周围细胞摄取的机制，是跨物种和相关的保守 到目前未知的机制在人脑中运作相关的神经退行性疾病 疾病我们正在利用C的巨大优势。elegans模型系统 （透明的身体，容易的基因操作，精致的神经系统，强大的细胞 生物学，寿命短），以促进对exopher生物学的理解。 最近一个有趣的进展是，我们发现关闭应激神经元的技巧 活动或联系实际上可以增加外泌体的产生。我们要求多样性 补充，使管理ADHA的杰出研究人员能够追求这方面的细节 生物学通过 我们的工作应该提供一种与健康大脑相关的细胞维持的新途径 衰老和神经退行性疾病，定义了一个新的研究和发展领域， 临床干预。

Alzheimer's disease is ravaging the world's elderly population and creating a heath and societal burden that appears likely to increase. Basic research can inform on mechanisms relevant to late onset neurodegenerative disease and suggest avenues of treatment. Healthy aging of the brain requires meticulous maintenance of protein synthesis/folding/degradation systems, and this capacity is often disrupted in neurodegenerative disease. Recently it has come to be appreciated that disease neurons can produce toxic products like aggregated proteins 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 send out large-sized extracellular material in vivo is an open question that must be addressed as we consider therapeutic intervention. We study the aging nervous system in the simple animal model C. elegans, in which individual neurons, as well as labeled aggregates within them, can easily be visualized in the living animal. We have unexpectedly discovered that some C. elegans neurons can exude large packets we call “exophers”. The contents of these dramatically expelled exophers can contain introduced human disease protein aggregates. Multiple approaches to exaggerating protein folding stresses in those neurons, including over-expressing human Alzheimer's disease associated fragment Abeta1-42, and genetically or pharmacologically impairing branches of protein homeostasis, increase exopher formation. Aggregated proteins extruded in exophers can be taken up by distant cells. We hypothesize that we have identified a previously unrecognized alternative route for adult neurons to clear protein aggregates. 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 neurodegenerative disease. We are exploiting the considerable advantages of the C. elegans model system (transparent body, easy genetic manipulation, exquisitely defined nervous system, powerful cell biology, short lifespan) to advance understanding of exopher biology. A fascinating recent development is our finding that tricks that shut down the stressed neurons activity or connection can actually increase exopher production. We request a Diversity Supplement to enable an outstanding researcher who manages ADHA to pursue details of this biology by Our work should inform on a novel pathway of cell maintenance relevant to both healthy brain aging and a neurodegenerative disease, defining a new area for study and for development of clinical interventions.