The Drosophila Eye: A model for protein trafficking in neurodegenerative disease

描述（由申请人提供）：本研究项目的长期目标是利用果蝇遗传学的力量来识别涉及年龄相关疾病的新基因和分子机制，如阿尔茨海默病（AD）和年龄相关性黄斑变性（AMD）。该项目特别关注蛋白质折叠、转运和靶向，以及这些高度调控过程中的缺陷如何导致与年龄相关的神经退行性病理。目标是了解衰老如何影响细胞环境并增强蛋白质积累的细胞毒性作用。异常蛋白质的加工和积累是许多眼部和脑部神经退行性疾病的罪魁祸首。在眼睛中，神经变性会导致致盲性疾病，如老年性黄斑变性。老年性黄斑变性是55岁以上人群视力丧失的主要原因。在大脑中，神经变性会导致认知障碍，如阿尔茨海默病。阿尔茨海默病仅在美国就影响了500多万人，是老年人中最常见的痴呆症。AMD和AD的病因尚不清楚，也没有治疗方法。虽然年龄显然是已知的最重要的风险因素，但遗传因素和其他几个因素可能也在起作用。果蝇遗传学的复杂性和广泛的知识基础使果蝇成为研究年龄相关疾病的强大动物模型。果蝇的寿命约为2个月，这使得人们可以在短时间内跟踪与年龄相关的变性的发生和发展。经历年龄相关视网膜变性的果蝇突变体将被用来揭示光感受器细胞中协调蛋白质生物合成的各种分子信号机制。提出的实验将采用遗传、生化、细胞生物学、分子和电生理方法的综合策略。目的1涉及一种新型高尔基网蛋白Gos28的表征及其在囊泡运输中的作用。目标2涉及鉴定和表征与gos28基因相互作用的其他位点，因此是蛋白质运输共享分子途径的一部分。最后，目的3涉及减缓神经变性的发病和进展的治疗方法的研究。与公共卫生相关：本文提出的研究以果蝇眼为模型，将为老年相关疾病（如阿尔茨海默病和老年黄斑变性）中蛋白质错误折叠和靶向缺陷的一般机制提供见解。这项提议的最终目标是了解蛋白质积累的细胞毒性作用，并利用这一知识来开发减缓与年龄相关的神经变性的发病和进展的治疗方法。

DESCRIPTION (provided by applicant): The long-term objective of this research project is to harness the power of Drosophila genetics to identify novel genes and molecular mechanisms involved in age-related diseases, such as Alzheimer's disease (AD) and age-related macular degeneration (AMD). The proposed project is specifically focused on protein folding, transport, and targeting and how defects in these highly regulated processes lead to age- related neurodegenerative pathology. A goal is to understand how aging influences the cellular environment and enhances the cytotoxic effects of protein accumulation. Aberrant protein processing and accumulation are the culprits in many neurodegenerative diseases in the eye and brain. In the eye, neurodegeneration leads to blinding disorders such as AMD. AMD is the leading cause of vision loss in people over the age of 55. In the brain, neurodegeneration leads to cognitive disorders such as AD. AD affects over 5 million people in the U.S. alone and is the most common form of dementia among older people. The bases of AMD and AD are not well understood and no cures are available. Although age is clearly the most important known risk factor, there is a strong genetic component and several factors are likely at play. This complexity and the broad base of knowledge in Drosophila genetics, combine to make Drosophila a powerful animal model for studying age-related disorders. The Drosophila life span is about 2 months, allowing one to follow the onset and progression of age-related degenerations in a short period of time. Drosophila mutants that undergo age-related retinal degeneration will be utilized to uncover diverse molecular signaling mechanisms that coordinate protein biosynthesis in photoreceptor cells. The proposed experiments will use an integrated strategy of genetic, biochemical, cell biological, molecular, and electrophysiological approaches. Aim 1 involves the characterization of a novel Golgi SNARE protein, Gos28, and its role in vesicular trafficking. Aim 2 involves the identification and characterization of additional loci that genetically interact with gos28, and are thus part of a shared molecular pathway for protein trafficking. Finally, aim 3 involves the investigation of therapeutic approaches for slowing the onset and progression of neurodegeneration. Relevance to Public Health: Studies proposed here, using the Drosophila eye as a model, will provide insights into the general mechanisms of protein misfolding and defective targeting in age-related diseases, such as Alzheimer's disease and age-related macular degeneration. The ultimate goal of this proposal is to understand the cytotoxic effects of protein accumulation and use this knowledge to develop treatments that slow down the onset and progression of age-related neurodegeneration.