Defining Roles of Genetics and Age in Extrusion of Neurotoxic Aggregates

阿尔茨海默病正在肆虐世界上的老年人口，并创造出一种健康和社会 看起来可能会增加的负担。基础研究可以为相关的机制提供信息 迟发性神经退行性疾病和建议的治疗途径。老年人的健康老龄化 大脑需要精心维护蛋白质合成/折叠/降解系统，以及 在神经退行性疾病中，这种能力经常被破坏。最近，它已经变得 认识到疾病神经元可以产生有毒产物，如聚集蛋白，可以 被邻近的细胞占据--有猜测认为这种机制可能 参与疾病在大脑中的传播。神经元如何产生和发出大规模的 活体细胞外物质是一个悬而未决的问题，必须在我们考虑时予以解决 治疗性干预。 我们研究了简单动物模型线虫的神经系统老化，在这个模型中，个体 在活着的动物身上，可以很容易地看到神经元以及其中标记的聚集体。 我们出人意料地发现，线虫的一些神经元可以分泌出大包我们 叫“外星人”。这些被戏剧性地驱逐的外星人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 这些神经元的应激，包括与阿尔茨海默病相关的人类阿尔茨海默病的过度表达 片段Abeta1-42，以及遗传或药物损伤的蛋白质分支 动态平衡，增加外溢物的形成。在胞外蛋白中挤出的聚集蛋白可以 被遥远的细胞占据。 我们假设我们已经确定了一条以前未被认可的成人替代路线 神经元清除蛋白质聚集体。我们推测，这一机制和相关的 周围细胞释放和摄取的机制在物种和相关物种中是保守的 到目前未知的人脑中与神经退行性变相关的机制 疾病。我们正在利用线虫模型系统的相当大的优势 (透明的身体，轻松的基因操作，精致的神经系统，强大的细胞 生物学，短寿命)，以促进对外星人生物学的理解。 最近一个有趣的发展是，我们发现关闭受压力的神经元的技巧 活动或联系实际上可以增加外溢物的产量。我们要求多样性 补充，使管理ADHA的杰出研究人员能够深入了解这一细节 生物学作者： 我们的工作应该揭示一种与健康大脑相关的细胞维持的新途径 衰老和一种神经退行性疾病，定义了一个研究和发展的新领域 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.