Synaptic dysfunction in neurodegenerative diseases

描述(申请人提供)：这个项目的长期目标是了解神经退行性疾病中突触功能障碍的潜在机制。突触功能障碍是神经退行性疾病的早期特征，在神经元死亡和临床症状出现之前。然而，突触恶化如何与疾病进展的后期阶段相关尚不清楚。有证据表明，突触功能障碍是可逆的，可以延缓细胞死亡，这突显了了解突触病理及其在神经退行性疾病中的作用的必要性。我们试图解决这个问题，使用果蝇来分析突触在神经退行性变之前和期间的结构和功能完整性。我们将重点研究支配背侧纵向飞行肌肉的神经肌肉接头(NMJ)，以检查这种突触病理。我们计划使用已建立的神经退行性变模型来分析突触，包括与神经退行性疾病有关的有毒蛋白的表达，以及果蝇神经退行性变突变体。这项分析将解决三个问题：1)突触在变性开始之前是如何受损的？2)突触功能障碍会导致神经变性吗？3)逆转这种功能障碍能防止神经元死亡吗？我们还计划利用RNAi转基因来识别与突触功能障碍和神经退行性变相关的新基因，并表征它们在退行性变中的作用。这项研究将帮助我们了解疾病发展的早期阶段，拓宽我们对神经元死亡的理解，并允许开发治疗神经退行性疾病的治疗靶点。 公共卫生相关性： 在了解神经退行性疾病的本质方面已经取得了很大进展，但绝大多数研究都专门集中在细胞死亡上，这是疾病进展的后期阶段。最近的证据表明，突触在临床症状出现之前很久就受到了影响。我们的目标是了解突触在神经退行性疾病中是如何受到不利影响的，并测试逆转这种突触病理是否可以防止或延缓神经元死亡。

DESCRIPTION (provided by applicant): The long-term objective of this project is to understand the mechanisms underlying synaptic dysfunction in neurodegenerative diseases. Synaptic dysfunction is an early hallmark of neurodegenerative diseases, preceding neuronal death and the onset of clinical symptoms. However, how synaptic deterioration relates to later stages of disease progression is unclear. Evidence suggests that synaptic dysfunction is reversible and can delay cell death, highlighting the need for understanding synaptic pathology and it's role in neurodegenerative diseases. We seek to address this issue using Drosophila to analyze the structural and functional integrity of synapses prior to and during neurodegeneration. We will focus on the neuromuscular junctions (NMJs) innervating the dorsal longitudinal flight muscles to examine this synaptic pathology. We plan to analyze synapses using established models of neurodegeneration, including expression of toxic proteins implicated in neurodegenerative diseases, as well as Drosophila neurodegeneration mutants. This analysis will address three questions: 1) How are synapses impaired prior to the onset of degeneration? 2) Does synaptic dysfunction cause neurodegeneration? 3) Does reversing this dysfunction prevent neuronal death? We also plan to identify novel genes involved in synaptic dysfunction and neurodegeneration using RNAi transgenes, and characterize their roles in degeneration. This research will help us to understand early stages of disease progression, broadening our understanding of neuronal death and allowing development of therapeutic targets to treat neurodegenerative diseases. PUBLIC HEALTH RELEVANCE: Much progress has been made on understanding the nature of neurodegenerative diseases, but the vast majority of studies have focused specifically on cell death, which is a late stage of disease progression. Recent evidence suggests that synapses are affected long before the onset of clinical symptoms. Our goal is to understand how synapses are adversely affected in neurodegenerative diseases, and test whether reversing this synaptic pathology can prevent or delay neuronal death.