Defining Roles of Genetics and Age in Extrusion of Neurotoxic Aggregates

定义遗传和年龄在神经毒性聚集体排出中的作用

基本信息

批准号：
10621615
负责人：
MONICA A. DRISCOLL
金额：
$ 11.37万
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/10621615
关键词：
Address Adult Age Aging Alzheimer&apos s Disease Amyloid beta-Protein Animal Model Animals Area Attention Attention deficit hyperactivity disorder Autophagocytosis Basic Science Biological Models Biology Brain Caenorhabditis elegans Caliber Cell Death Cell Maintenance Cells Cellular biology Chloride Channels Data Development Disease Distant Elderly Functional disorder Future Generations Genetic Goals Health Histamine Human Impairment Individual Intervention Label Longevity Maintenance Membrane Membrane Potentials Modeling Molecular Molecular Chaperones Nanotubes Nerve Degeneration Nervous system structure Neurodegenerative Disorders Neurons Parents Pathogenicity Pathologic Pathology Pathway interactions Pharmacology Phase Physiological Population Postdoctoral Fellow Process Production Property Protein Biosynthesis Proteins Reagent Regulation Research Activity Research Personnel Role Route Sensory Process Signal Transduction Stress Structure Subcutaneous Tissue Synapses System Therapeutic Therapeutic Intervention Time Touch sensation Training Support Vesicle Work age related neurodegeneration aging brain clinical development effective intervention endoplasmic reticulum stress experience extracellular fascinate fly functional decline genetic manipulation healthy aging human disease in vivo multicatalytic endopeptidase complex neural network neuronal cell body neuronal survival neurotoxic novel parent grant polyglutamine protein aggregation protein folding proteostasis proteotoxicity uptake

项目摘要

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 Abeta1-42, 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 are exploiting 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. A fascinating recent development is our finding that tricks that shut down the stressed neurons activity or connection can actually increase exopher production. We request a Diversity Supplement to enable an outstanding researcher who manages ADHA to pursue details of this biology by 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.

阿尔茨海默氏病正在破坏世界的古老人口，并创造荒地和社会伯恩似乎有可能增加。基础研究可以告知与后来发作神经退行性疾病，并提出治疗途径。健康的老化大脑需要细致维护蛋白质合成/折叠/降解系统，并且这种能力通常在神经退行性疾病中受到破坏。最近它已经成为理解疾病神经元可以生产有毒产品，例如综合蛋白被邻近细胞吸收 - 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体内的细胞外材料是一个开放的问题，必须在我们考虑的情况下解决治疗干预。我们研究了简单动物模型C.秀隐素的衰老神经系统，其中个体神经元以及其中的标记骨料可以很容易地在活的动物中可视化。我们意外地发现，一些秀丽隐杆线虫神经元可以超过我们称为“流浪者”。这些巨大探索的传口的内容可以包含引入的人类疾病蛋白骨料。多种夸大蛋白质折叠的方法这些神经元的压力，包括过度表达人类阿尔茨海默氏病片段Abeta1-42，以及遗传或药物损害蛋白质的分支体内平衡，增加外生的形成。挤出物中挤出的蛋白质可以是被远处的细胞占用。我们假设我们已经确定了成人先前未认可的替代途径神经元清除蛋白质聚集体。我们推测这种机制以及相关的周围细胞的释放和摄取机制是在物种及相关的目前在与神经退行性相关的人脑中运作的未知机制疾病。我们正在利用秀丽隐杆线虫模型系统的可观优势（透明的身体，易于遗传操作，精确定义神经系统，强大的细胞生物学，寿命短），以提高对外生物学的了解。最近的一个令人着迷的发展是我们的发现，这些技巧使紧张的神经元关闭了活动或连接实际上可以增加外源产量。我们要求多样性补充以启用一个杰出的研究人员，该研究人员管理ADHA购买有关此详细信息的详细信息生物学作者我们的工作应该告知与健康大脑相关的细胞维护途径衰老和神经退行性疾病，定义了一个新的研究领域和发展临床干预措施。