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与年龄相关疾病（如阿尔茨海默病（AD）和年龄相关性黄斑变性（AMD））相关的新基因和分子机制。拟议的项目是专门集中在蛋白质折叠，运输和靶向，以及如何在这些高度调控的过程中的缺陷导致年龄相关的神经退行性病变。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。异常的蛋白质加工和积累是眼睛和大脑中许多神经退行性疾病的罪魁祸首。在眼睛中，神经变性导致致盲性疾病，如AMD。AMD是55岁以上人群视力丧失的主要原因。在大脑中，神经变性导致认知障碍，如AD。AD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的基础还没有很好的理解，也没有治愈方法。虽然年龄显然是最重要的已知风险因素，但有很强的遗传成分，可能有几个因素在起作用。这种复杂性和果蝇遗传学知识的广泛基础，联合收割机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，允许人们在短时间内跟踪与年龄相关的退化的发生和进展。果蝇发生年龄相关性视网膜变性的突变体将被用来揭示感光细胞中协调蛋白质生物合成的多种分子信号机制。拟议的实验将使用遗传，生物化学，细胞生物学，分子和电生理方法的综合战略。目的1涉及一种新的高尔基体陷阱蛋白，Gos28，其在囊泡运输的作用的特点。目标2涉及鉴定和表征与gos 28基因相互作用的其他基因座，因此是蛋白质运输的共享分子途径的一部分。最后，目标3涉及减缓神经退行性变的发作和进展的治疗方法的研究。与公共卫生的相关性：这里提出的研究，使用果蝇眼睛作为模型，将提供深入了解蛋白质错误折叠的一般机制和老年性疾病，如阿尔茨海默病和年龄相关性黄斑变性的缺陷。该提案的最终目标是了解蛋白质积累的细胞毒性作用，并利用这些知识开发减缓年龄相关神经退行性变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.