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: 10597235
• 负责人: MONICA A. DRISCOLL
• 金额: $ 53.71万
• 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 2027-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10597235
• 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; Neurodegenerative Disorders; Neuronal Dysfunction; Neurons; Orthologous Gene; Outcome; Pathogenesis; Pathology; Pathway interactions; 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; Visualization; Work; aging brain; aging population; clinical development; extracellular; genetic manipulation; genome wide association study; healthy aging; human disease; human old age (65+); in vivo; insight; knock-down; longevity gene; middle age; misfolded protein; multicatalytic endopeptidase complex; neuronal cell body; neuroprotection; neurotoxic; novel; overexpression; pharmacologic; polyglutamine; protein aggregation; protein folding; proteostasis; proteotoxicity; response; screening; segregation; 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.

概括 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。基础研究可以为晚发性神经退行性疾病的相关机制提供信息 疾病并提出治疗途径。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。最近人们认识到疾病神经元可以产生有毒产物，例如 可以被邻近细胞吸收的聚集蛋白——有人猜测这种机制可能 参与大脑内疾病的传播。神经元如何产生和发出大尺寸的细胞外物质 体内材料是一个悬而未决的问题，在我们考虑治疗干预时必须解决。 我们研究了简单动物模型秀丽隐杆线虫的衰老神经系统，其中单个神经元，如 以及其中标记的聚集体，可以在活体动物中轻松观察到。我们有意想不到的 发现一些秀丽隐杆线虫神经元可以分泌出大的包，我们称之为“exophers”。这些内容 显着排出的外泌体可能含有引入的人类疾病蛋白质聚集体。多种的 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 A 1-42，以及遗传或药理学受损的分支 蛋白质稳态，增加外层形成。 exophers中挤出的聚集蛋白可以被吸收 由遥远的细胞。 我们假设我们已经确定了一种以前未被识别的成人神经元清除的替代途径 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 由周围细胞产生，在物种之间是保守的，并且与目前未知的机制有关 人脑与神经退行性疾病相关。 我们建议利用线虫模型系统的相当大的优势（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、短寿命）来推进 对 exopher 生物学​​的了解。我们的目标是：1）探索老年外显者的生物学（归纳， 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 线虫 exopher 形成中的作用； 3）开始破译AIP-1的机制，所需的 exopher 的产生并已知可防止广泛的蛋白质毒性，影响 exopher 的发生 蛋白质应激。 我们的工作应该揭示一种与健康的大脑衰老和大脑健康相关的细胞维护的新途径。 神经退行性疾病，定义了研究和临床干预开发的新领域。