Synaptic dysfunction in neurodegenerative diseases

描述（由申请人提供）：本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标志，先于神经元死亡和临床症状的发作。然而，突触退化如何与疾病进展的后期阶段有关尚不清楚。有证据表明，突触功能障碍是可逆的，可以延迟细胞死亡，强调需要了解突触病理学及其在神经退行性疾病中的作用。我们试图解决这个问题，使用果蝇来分析突触的结构和功能的完整性之前和期间的神经变性。我们将集中在神经肌肉接头（NMJs）支配的背纵飞行肌肉检查这种突触病理。我们计划使用已建立的神经变性模型分析突触，包括神经变性疾病中涉及的毒性蛋白的表达，以及果蝇神经变性突变体。该分析将解决三个问题：1）在变性开始之前突触是如何受损的？2)突触功能障碍会导致神经退行性变吗？3)逆转这种功能障碍能防止神经元死亡吗？我们还计划使用RNAi转基因来鉴定参与突触功能障碍和神经变性的新基因，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，扩大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.