Synaptic dysfunction in neurodegenerative diseases

描述（由申请人提供）：该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机制。突触功能障碍是神经退行性疾病的早期标志，发生在神经元死亡和临床症状出现之前。然而，突触退化与疾病进展后期的关系尚不清楚。有证据表明，突触功能障碍是可逆的，并且可以延迟细胞死亡，这凸显了了解突触病理学及其在神经退行性疾病中的作用的必要性。我们试图利用果蝇来分析神经变性之前和过程中突触的结构和功能完整性来解决这个问题。我们将重点关注支配背侧纵向飞行肌的神经肌肉接头（NMJ）来检查这种突触病理学。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突变体。该分析将解决三个问题：1）突触在退化开始之前是如何受损的？ 2）突触功能障碍是否会导致神经退行性变？ 3）逆转这种功能障碍是否可以防止神经元死亡？我们还计划利用 RNAi 转基因鉴定与突触功能障碍和神经变性有关的新基因，并表征它们在变性中的作用。这项研究将帮助我们了解疾病进展的早期阶段，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。

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.