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

确定遗传和年龄在细胞外消除神经毒性聚集体中的作用

• 批准号: 9905340
• 负责人: MONICA A. DRISCOLL
• 金额: $ 46.2万
• 依托单位: RUTGERS, THE STATE UNIV OF N.J.
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-01 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9905340
• 关键词: ABI2 gene; Address; Adult; Affect; Age; Aging; Alzheimer' s Disease; Animal Model; Animals; Area; Autophagocytosis; Basic Science; Biological Models; Biology; Brain; Caenorhabditis elegans; Cell Maintenance; Cells; Cellular biology; Chronology; Data; Disease; Dissection; Distant; Elderly; Elements; Functional disorder; Genes; Genetic; Goals; Health; Homologous Gene; Human; Human Pathology; Impairment; Individual; Intervention; Label; Life; Longevity; Maintenance; Mammals; Membrane; Microscope; Modeling; Molecular; Molecular Chaperones; Molecular Conformation; Nerve Degeneration; Nervous system structure; Neurodegenerative Disorders; Neuronal Dysfunction; Neurons; Orthologous Gene; Outcome; Pathogenesis; Pathology; Pathway interactions; Pharmacology; Physiological; Play; Population; Process; Production; Protein Biosynthesis; Proteins; Publishing; Quality Control; RNA Interference; Role; Route; Stress; Structure; System; Testing; Therapeutic; Therapeutic Intervention; Toxic effect; Transgenes; Vesicle; Work; aging brain; aging population; clinical development; extracellular; genetic manipulation; genome wide association study; healthy aging; human disease; in vivo; insight; knock-down; longevity gene; middle age; misfolded protein; multicatalytic endopeptidase complex; neuronal cell body; neuroprotection; neurotoxic; novel; overexpression; polyglutamine; protein aggregation; protein folding; proteostasis; proteotoxicity; response; screening; uptake

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.

总结 阿尔茨海默病正在肆虐世界老年人口，并造成健康和社会负担， 似乎有可能增加。基础研究可以为迟发性神经退行性变相关机制提供信息 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，这种能力往往在神经退行性疾病中被破坏。 疾病最近人们认识到，疾病神经元可以产生有毒产物， 聚集的蛋白质可以被邻近的细胞吸收-有推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 在我们考虑治疗干预时，体内材料是一个必须解决的开放性问题。 我们用简单的动物模型C.其中单个神经元，如 以及它们内部的标记聚集体，可以很容易地在活体动物中观察到。我们意外地 发现一些C.线虫的神经元可以分泌出我们称之为“外泌体”的大包。其中的内容 显著排出的外泌体可含有引入的人类疾病蛋白质聚集体。多 夸大这些神经元中蛋白质折叠应力的方法，包括过度表达人类 阿尔茨海默氏病相关片段A1 -42，以及遗传或神经功能损害的分支， 蛋白质稳态增加外泌体形成在胞外体中挤出的聚集蛋白质可以被吸收 遥远的细胞。 我们假设，我们已经确定了一个以前未被认识的替代途径，成年神经元清除 蛋白质聚集体。我们推测，这种机制，以及相关的释放和摄取机制， 通过周围的细胞，是保守的跨物种和有关目前未知的机制运作， 人类大脑与神经退行性疾病有关。 我们建议充分利用C. elegans模型系统（透明体，简单 基因操纵，精确定义的神经系统，强大的细胞生物学，短寿命）， 了解外泌体生物学。我们的目标是：1）探索老年exophers的生物学（诱导， 功能和长寿基因界面）; 2）筛选人类神经退行性疾病相关基因， 角色在C。3）开始破译AIP-1的机制，AIP-1是线虫外泌体形成所必需的。 外泌体的产生和已知的保护广泛的蛋白质毒性，影响外泌体的发生， 蛋白应激 我们的工作应该提供一种新的细胞维持途径，这种途径与健康的大脑衰老和衰老有关。 神经退行性疾病，定义了一个新的研究领域和临床干预措施的发展。