Defining roles of genetic and age in extracellular elimination of neurotoxic aggregates

摘要 阿尔茨海默病正在肆虐世界上的老年人口，并造成健康和社会负担 看起来可能会增加。基础研究可以为迟发性神经退行性变的相关机制提供信息 疾病和建议的治疗途径。大脑的健康老化需要精心维护 蛋白质合成/折叠/降解系统，这种能力在神经退行性疾病中经常被破坏 疾病。最近，人们逐渐认识到，疾病神经元可以产生有毒的产物，如 可以被邻近细胞摄取的聚集蛋白质--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细胞外信号 体内材料是一个悬而未决的问题，当我们考虑治疗干预时必须解决这个问题。 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，单个神经元，如 以及它们内部的标记聚集体，可以很容易地在活着的动物身上可视化。我们出乎意料地拥有 发现线虫的一些神经元可以散发出我们称之为“外显”的大包。这些文件的内容 被戏剧性地排出的外显物可能含有引入的人类疾病蛋白质聚集体。多重 夸大这些神经元中蛋白质折叠压力的方法，包括过度表达人类 阿尔茨海默病相关片段A1-42，以及遗传或药物损害的分支 蛋白质动态平衡，增加外膜形成。在胞外挤出的聚集蛋白质可以被吸收。 由遥远的手机发出。 我们假设，我们已经确定了一种以前未被发现的替代途径，供成年神经元清除 蛋白质聚集体。我们推测，这一机制以及与之相关的释放和摄取机制 通过周围的细胞，在物种之间是保守的，并与目前未知的机制有关 人类大脑与神经退行性疾病有关。 我们建议利用线虫模型系统的显著优势(透明的身体，容易 基因操作、精确定义的神经系统、强大的细胞生物学、短暂的寿命)来推动 了解外星人生物学。我们的目标是：1)探索老年外显者的生物学(诱导， 功能和长寿基因接口)；2)筛选人类神经退行性疾病相关基因 在线虫外排体形成中的作用；3)开始破译AIP-1，所需的 外膜的产生和已知可防止广泛的蛋白毒性，影响外膜的发生。 蛋白质重音。 我们的工作应该揭示一种新的细胞维持途径，与健康的大脑衰老和 神经退行性疾病，为研究和开发临床干预措施定义了一个新的领域。

Summary 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 A 1-42, 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 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 advance understanding of exopher biology. Our goals are to: 1) probe the biology of old age exophers (induction, functionality, and longevity gene interface); 2) screen human neurodegenerative disease-related genes for roles in C. elegans exopher formation; 3) begin to decipher the mechanism whereby AIP-1, needed for exopher production and known to protect against broad proteotoxicity, influences exopher-genesis under proteo-stress. 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.