Molecular Mechanisms linking Aging, Abeta Proteotoxicity and Neurodegeneration

描述（由申请人提供）：衰老会增加神经退行性变的风险。强有力的证据表明，聚集介导的蛋白毒性是许多临床重要疾病（包括阿尔茨海默病）神经退行性变的原因，尽管病因尚不清楚。新出现的遗传数据表明，衰老过程通过信号通路与蛋白质稳态的保真度相联系，包括恢复或处理错误折叠或聚集蛋白质的能力。总的来说，该计划项目致力于实现两个目标：1）了解保护生物体免受蛋白质聚集的途径的生物体，细胞生物学和分子基础，以及2）确定这些途径如何随着生物体年龄的增长而受到损害。凯利实验室将专注于途径的生化特征和解聚酶活性的潜在分子决定因素，这些分子决定因素似乎可以保护C.他们将测试淀粉样蛋白生成是一个组成性过程的假设。Balch实验室将生成衰老细胞模型，以探索外泌和内吞APR和Abeta处理中年龄依赖性变化的作用，这些变化似乎有助于蛋白毒性，并将利用他们的专业知识来扰乱外泌和内吞途径，以了解Abeta蛋白毒性的起源。Dillin实验室将利用遗传学、蛋白质组学和生物信息学方法以及阿尔茨海默病的动物模型来了解衰老相关的信号通路和下游决定因素如何影响蛋白质毒性，并将在蠕虫阿尔茨海默病模型中进行Abeta聚集体结构毒性评估。生物信息学、蛋白质组学、神经科学和神经病理学的核心都与两个或多个这些项目密切相关，而这些项目本身又高度相互依赖。从该项目中获得的结果不仅将提供对衰老和神经退行性疾病之间关系的深入了解，而且还将为开发与年龄相关的神经退行性疾病的治疗策略提供必要的信息。

DESCRIPTION (provided by applicant): Aging increases the risk of neurodegeneration. Strong evidence implicates aggregation-mediated proteotoxicity as the cause of neurodegeneration in numerous clinically important diseases, including Alzheimer's disease, although the etiology is unclear. Emerging genetic data suggest that the aging process is linked by signaling pathways to the fidelity of protein homeostasis, including the ability to recover or dispose of misfolded or aggregated proteins. Overall this program project strives to meet two goals: 1) to understand the organismal, cell biological and molecular bases for the pathways that protect organisms from protein aggregation, and 2) to determine how these pathways become compromised as an organism ages. The Kelly Laboratory will focus on the biochemical characterization of the pathway(s) and the underlying molecular determinants of the disaggregase activity that appears to protect against age onset proteotoxicity in C. elegans and murine models of Alzheimer's and in human cells and they will test the hypothesis that amyloidogenesis is a constitutive process. The Balch Laboratory will generate senescence cell models to probe the role of age-dependent changes in exocytic and endocytic APR and Abeta processing that appear to contribute to proteotoxicity and will employ their expertise to perturb the exocytic and endocytic pathways to understand the genesis of Abeta proteotoxicity. The Dillin Laboratory will utilize genetic, proteomic and bioinformatics approaches and animal models of Alzheimer's disease to understand how and which aging-associated signaling pathways and downstream determinants affect proteotoxicity and they will carry out Abeta aggregate structure toxicity assessments in the worm Alzheimer's model. The bioinformatics, proteomics and neurosciences and neuropathology cores are each intimately associated with two or more of these projects that are themselves highly interdependent. The results obtained from this project will not only provide insight into the relationship between aging and neurodegeneration, but should provide the information necessary to develop therapeutic strategies for age-associated neurodegenerative diseases.