Understanding the Mechanisms of Neuropathogenesis

描述（由申请人提供）：本研究计划的长期目标是了解调节后生动物中年龄依赖性神经元活力的生化途径。使用一个易于处理的遗传系统来阐明这些途径，并揭示它们导致神经退行性疾病和正常衰老的机制，是我研究的重要目标。我们已经分离出一些突变体在一个公正的正向遗传筛选，为我们提供了一个新的角度来研究神经元的衰老和神经退行性变在体内。该提案的重点是影响ATPalpha（Na/K ATP酶）的突变，这会导致果蝇进行性神经变性。在人类中，Na/K ATP酶功能丧失突变导致快速发作的肌张力障碍性帕金森综合征（RDP）和家族性偏瘫性偏头痛（FHM）。Na/K ATP酶活性在缺血和创伤性脑损伤后降低，并且与阿尔茨海默病相关。我们假设，神经发病机制是在我们的突变体和神经系统疾病，包括RDP和FHM患者的机制相似，并提出实验来阐明这些机制的细节。此外，我们建议确定能够抑制潜在的功能障碍和神经退行性变的突变。我们将使用遗传、分子、细胞生物学和生物化学技术研究这些突变体，以阐明突变导致细胞功能障碍的机制，并发现这种功能障碍如何表现为神经学表型，如瘫痪、癫痫发作和进行性神经变性。这些具体的实验将阐明ATPalpha突变体的神经发病机制，并导致更好地了解年龄相关的神经退行性变和衰老。

DESCRIPTION (provided by applicant): The long-term goal of this research program is to understand the biochemical pathways that regulate age-dependent neuronal viability in metazoans. Using a tractable genetic system to elucidate these pathways and uncover the mechanisms by which they contribute to neurodegenerative diseases and normal senescence, are important goals of my research. We have isolated a number of mutants in an unbiased forward genetic screen that provide us a novel perspective with which to study neuronal senescence and neurodegeneration in vivo. This proposal focuses on mutations that affect ATPalpha (Na/K ATPase), which cause progressive neurodegeneration in Drosophila. In humans loss-of-function Na/K ATPase mutations cause Rapid-onset Dystonia Parkinsonism (RDP) and familial hemiplegic migraines (FHM). Na/K ATPase activity is reduced after ischemia and traumatic brain injury, and is associated with Alzheimer's disease. We hypothesize that neuropathogenesis is mechanistically similar in our mutants and patients with neurological diseases, including RDP and FHM, and propose experiments to elucidate these mechanistic details. Additionally, we propose to identify mutations capable of suppressing the underlying dysfunction and neurodegeneration. We will study these mutants using genetic, molecular, cell biological, and biochemical techniques to elucidate the mechanisms by which the mutations lead to cellular dysfunction and discover how this dysfunction manifests as neurological phenotypes, such as paralysis, seizures and progressive neurodegeneration. Together these specific experiments will elucidate the mechanisms of neuropathogenesis in ATPalpha mutants and lead to a better understanding of age-related neurodegeneration and senescence.