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：
10813264
负责人：
MONICA A. DRISCOLL
金额：
$ 15.16万
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 2027-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10813264
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 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

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.

概括阿尔茨海默氏病正在肆虐世界上的人口，并创造了一种荒地和社会燃烧似乎有可能增加。基础研究可以告知与晚期神经退行性相关的机制疾病并提出治疗途径。大脑的健康衰老需要细致的维护蛋白质合成/折叠/降解系统，这种能力通常在神经退行性中被破坏疾病。最近，人们对疾病神经元可以生产有毒产品（例如可以用相邻细胞吸收的汇总蛋白质 - 猜测这种机制可能参与疾病在大脑中传播。神经元如何产生和发送大型细胞外体内材料是一个空旷的问题，当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中的衰老神经系统，其中单个神经元作为就像其中的标记聚集体一样，可以在活的动物中可以看到。我们出乎意料发现一些秀丽隐杆线虫神经元可以散发出我们称为“外源”的大包装。这些内容动态探索的外源可以包含引入的人类疾病蛋白聚集体。多种的夸大这些神经元中蛋白质折叠应力的方法，包括过度表达的人阿尔茨海默氏病与1-42相关的片段，以及遗传或物理上损害的分支蛋白质稳态，增加外牙形成。可以吸收挤出在外的蛋白质通过远处的细胞。我们假设我们已经确定了成人神经元清除的先前未认可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吸收机制通过周围的细胞，跨物种保守，并且与目前未知的机制有关与神经退行性疾病有关的人脑。我们建议探索秀丽隐杆线虫模型系统的可观优势（透明的身体，简单基因操纵，精确定义神经系统，强大的细胞生物学，寿命短）对外生物学的理解。我们的目标是：1）探究老年传送者的生物学（归纳，功能和寿命基因界面）； 2）筛选人类神经退行性疾病相关的基因秀丽隐杆线虫的角色外虫形成； 3）开始破译AIP-1所需的机制外生生产并已知可以防止广泛的蛋白质毒性，影响了外生成蛋白质压力。我们的工作应告知与健康的脑衰老和A相关的细胞维持途径神经退行性疾病，定义了一个新的研究领域和临床干预措施的发展。