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

基本信息

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
项目类别：
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&apos 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

项目摘要

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，基础研究似乎可能会增加有关迟发性神经退行性疾病的机制。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——有人推测这种机制可能参与大脑内疾病的传播。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，我们可以轻松地在活体动物中观察到。发现一些秀丽隐杆线虫神经元可以分泌出大包我们称之为“exophers”的内容物。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。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，增加外蛋白形成，外蛋白中挤出的聚集蛋白可以被吸收。由遥远的细胞。我们探索发现，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）来推进我们的目标是：1）探索老年 exopher 的生物学（归纳， 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 所需的机制 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。