Mechanisms Underlying Neuronal Cell Type Specificity in Neurodegeneration

描述（由申请人提供）：帕金森病、阿尔茨海默病等神经退行性疾病患者的症状非常明显。每种疾病的特征性临床表现的基础是不同神经元细胞群的功能障碍和死亡。然而，尽管我们对神经退行性疾病的理解在分子遗传学、病理学和生化方面取得了许多重要进展，但神经元细胞类型特异性的基础仍然是一个根本的谜。我们将采取遗传方法来解决有丝分裂后神经元亚群特异性变性的问题。我们的方法将是在果蝇中进行无偏见的前向遗传筛选，以概述分化的成年神经元中负责细胞类型特异性神经变性的途径。我们将概述维持正常神经元和表达与阿尔茨海默病和帕金森病有关的有毒蛋白的神经元亚群活力的途径。重要的是，我们之前已经在帕金森病和阿尔茨海默病模型中证明了相关的神经元细胞类型特异性变性。在果蝇系统中开发的候选人类同源物将被检查在人体组织中脆弱神经元的解剖定位。从长远来看，在目前的建议中确定的神经元易感性的细胞类型特异性途径将为阿尔茨海默病，帕金森病和相关神经退行性疾病提供有吸引力的治疗靶点。公共卫生相关性：医生和家属都知道，阿尔茨海默病患者通常会出现记忆丧失和其他认知问题，而帕金森病通常表现为震颤、行动迟缓和僵硬。尽管我们知道这些特征性疾病症状反映了这些患者大脑中特定神经元的丢失，但我们对特定疾病中特定神经元亚群丢失的原因知之甚少。我们的研究旨在确定特定神经元特异性丧失的机制，作为设计有效治疗这些破坏性疾病的长期努力的一部分。

DESCRIPTION (provided by applicant): The symptoms experienced by patients with neurodegenerative disorders like Parkinson's disease, Alzheimer's disease and other less common conditions are quite distinct. The basis for the characteristic clinical manifestations of each of the disorders is dysfunction and death of different neuronal cell populations. However, despite many important molecular genetic, pathological and biochemical advances in our understanding of neurodegenerative diseases, the basis for neuronal cell type-specificity remains a fundamental mystery. We will take a genetic approach to the problem of specific degeneration of subsets of postmitotic neurons. Our approach will be to perform unbiased forward genetic screens in Drosophila to outline pathways responsible for cell type-specific neurodegeneration in differentiated adult neurons. We will outline pathways that maintain viability of subsets of neurons both in otherwise normal neurons and in neurons expressing toxic proteins implicated in Alzheimer's and Parkinson's disease. Importantly, we have previously demonstrated relevant neuronal cell type-specific degeneration in our Parkinson's and Alzheimer's disease models. Human homologs of candidates developed in the Drosophila system will then be examined for anatomic localization to vulnerable neurons in human tissue. In the longer term, the cell type-specific pathways of neuronal vulnerability identified in the current proposal will provide attractive therapeutic targets in Alzheimer's disease, Parkinson's disease and related neurodegenerative disorders. PUBLIC HEALTH RELEVANCE: As doctors and family members alike know, patients with Alzheimer's disease often experience loss of memory and other cognitive problems while Parkinson's disease is usually manifest by tremor, slowness of movement and rigidity. Although we know that these characteristic disease symptoms reflect loss of specific neurons in the brains of these patients, we have very little insight into why specific subsets of neurons are lost in particular diseases. Our studies seek to determine the mechanisms that underlie specific loss of identified neurons as part of a longer term effort to devise effective treatments for these devastating disorders.