Mechanisms Underlying Neuronal Cell Type Specificity in Neurodegeneration

描述（由申请人提供）：患有神经退行性疾病（如帕金森病、阿尔茨海默病和其他不太常见的疾病）的患者所经历的症状非常不同。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，尽管在我们对神经退行性疾病的理解中有许多重要的分子遗传学、病理学和生物化学进展，但神经元细胞类型特异性的基础仍然是一个根本的谜。我们将采取遗传学的方法来解决有丝分裂后神经元亚群的特异性变性问题。我们的方法将是在果蝇中进行无偏的正向遗传筛选，以概述负责分化的成年神经元中细胞类型特异性神经变性的途径。我们将概述维持神经元亚群的活力的途径，在其他正常的神经元和表达与阿尔茨海默氏症和帕金森氏症有关的毒性蛋白的神经元。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的人类同源物，然后将被检查解剖定位到人体组织中脆弱的神经元。从长远来看，在目前的建议中确定的神经元脆弱性的细胞类型特异性途径将为阿尔茨海默病，帕金森病和相关的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：正如医生和家人所知，阿尔茨海默病患者经常会出现记忆力丧失和其他认知问题，而帕金森病通常表现为震颤、运动缓慢和僵硬。虽然我们知道这些特征性的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子集丢失的原因知之甚少。我们的研究试图确定的神经元的特定损失的机制，作为长期努力的一部分，为这些毁灭性的疾病设计有效的治疗方法。

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.