Mechanisms modulating the maintenance of structural integrity in individual aging

描述(申请人提供)：老化的人脑中的细微变化，如神经元发芽和重组，被认为是认知能力下降的基础，并可能促进阿尔茨海默氏症和其他晚发型神经退行性疾病的神经元功能障碍。目前，我们对这些过程及其后果的了解太少，无法利用知识来设计治疗干预。我们研究线虫中与神经元衰老相关的基本过程。在这个透明的959细胞动物中，我们可以直接观察到单个荧光标记的神经元，以及荧光标记的蛋白质聚集体和线粒体。最近，我们仔细记录了线虫的一些神经元是如何随着动物的衰老而发生物理变化的。我们发现，就像人类大脑老化一样，线虫衰老时神经元几乎不会丢失。然而，随着年龄的增长，某些类型的神经元表现出戏剧性的新奇分支和突起；这些神经元的功能可能已经减弱。我们可以使用高倍解剖显微镜对这种与年龄相关的戏剧性树突重组进行评分，这有助于相对快速地分析活的、老化的动物中的单个神经元。确定成人神经系统维持其结构完整性的机制，并阐述鲜为人知的与年龄相关的树突重建机制，对于正常衰老和神经退行性疾病都是相当重要的。我们将结合使用荧光记者和遗传操作来解决三个目标：目标1是确定单个老化神经元中蛋白稳定中断和树突重构的关系；目标2是定义单个衰老神经元中线粒体状态和与年龄相关的树突重构之间的关系。这项研究还将在描述自然环境下单个神经元中老化的线粒体群体的基本细胞生物学方面开辟新的天地。目标3是筛选候选基因组，以确定影响老化神经系统结构完整性维持的新因素。我们的研究应该解决对在成熟神经系统中完成结构维护的基本生物学方面的理解差距，并提供可能更好地维持老化的人类神经系统的完整性和功能的机制和干预措施。

DESCRIPTION (provided by applicant): Subtle changes in the aging human brain, such as neuronal sprouting and restructuring, are thought to underlie cognitive decline and may promote neuronal dysfunction in Alzheimer's and other late-onset neurodegenerative disease. Currently we understand too little of these processes and their consequences to harness knowledge for design of therapeutic intervention. We study fundamental processes relevant to neuronal aging in C. elegans. In this transparent 959-celled animal, we can directly observe individual fluorescently labeled neurons, as well as fluorescently tagged protein aggregates and mitochondria. Recently, we carefully documented how some C. elegans neurons physically change as animals grow old. We find that like human brain aging, there is little neuron loss as C. elegans ages. However, some types of neurons exhibit dramatic novel branching and outgrowth with age; such neurons might have diminished function. We can score this dramatic age-associated dendritic restructuring using a high-magnification dissecting microscope, which facilitates relatively rapid analysis of individual neurons within live, aging animals. Defining th mechanisms by which adult nervous systems maintain their structural integrity and elaborating on the poorly understood mechanisms of age-associated dendritic restructuring is of considerable importance to both normal aging and neurodegenerative disease. We will combine use of fluorescent reporters with genetic manipulations to address three aims: Aim 1 is to define the relationship of proteostasis disruption and dendritic restructuring in individual aging neurons Aim 2 is to define the relationship between mitochondrial status and age-associated dendritic restructuring in individual aging neurons. This study will also break new ground in characterizing the basic cell biology of the aging mitochondrial populations in individual neurons in native context. Aim 3 is to screen candidate gene sets to identify novel factors that influence the maintenance of structural integrity of the aging nervous system. Our studies should address gaps in understanding of the basic biology by which structural maintenance is accomplished in a mature nervous system and inform on mechanisms and interventions that may better maintain the integrity and function of the aging human nervous system.