Mechanisms Underlying Neuronal Cell Type Specificity in Neurodegeneration

描述(申请人提供)：患有神经退行性疾病的患者，如帕金森氏病、阿尔茨海默病和其他不常见的疾病，其症状相当不同。每种疾病的独特临床表现的基础是不同神经细胞群体的功能障碍和死亡。然而，尽管我们在了解神经退行性疾病方面取得了许多重要的分子遗传学、病理学和生物化学方面的进展，但神经元细胞类型特异性的基础仍然是一个基本的谜团。我们将采用遗传学的方法来解决有丝分裂后神经元亚群的特定退化问题。我们的方法将是在果蝇中进行无偏见的正向遗传筛选，以勾勒出导致分化的成年神经元中细胞类型特定的神经退化的途径。我们将概述在其他正常神经元中以及在表达与阿尔茨海默氏症和帕金森氏病有关的有毒蛋白的神经元中维持神经元亚群活性的途径。重要的是，我们之前已经在帕金森氏症和阿尔茨海默病模型中展示了相关的神经细胞类型特异性变性。然后，将对在果蝇系统中开发的候选人类同源物进行解剖定位，以确定人类组织中脆弱的神经元的位置。从长远来看，当前提案中确定的神经元脆弱性的特定细胞类型的通路将为阿尔茨海默病、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。与公共卫生相关：正如医生和家人都知道的那样，阿尔茨海默病患者通常会出现记忆力丧失和其他认知问题，而帕金森氏病通常会表现为震颤、行动迟缓和僵硬。尽管我们知道这些典型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亚群丢失的原因知之甚少。我们的研究试图确定特定的已识别神经元丢失的机制，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.