2023-01-012024-05-13https://scholars.lib.ntu.edu.tw/handle/123456789/652240突觸前蛋白 α-突觸核蛋白 (αSyn) 的細胞質聚集體是多種神經退化性疾病的標誌特徵，包括帕金森病 (PD)。 αSyn 組裝成聚集體，沉積為路易體，導致黑質緻密部 (SNc) 中的多巴胺 (DA) 神經元死亡，影響運動控制並伴有便秘、視力缺陷、抑鬱或癡呆等症狀。在過去的二十年中，已證實αSyn 聚集和傳播與家族性和偶發性 PD 的發病有關。在人腦脊髓液中可檢測到細胞外 αSyn，表明致病性 αSyn 可能通過神經元間突觸的傳遞，傳播跨越大腦、眼睛，甚至腸道神經元，進一步破壞各種生理功能。因此，長期以來，人們一直期望研發出有效的干預措施來消耗致病性 αSyn 聚集體，從而抑制致病性 αSyn 突變體的傳播。然而，迄今為止，αSyn 聚集體傳播的基本機制在很大程度上仍然未知，故未能找出潛在的干預措施；因此， 本研究旨在探討致病性人類 αSyn 傳播的機制。我們由之前建立的大鼠 PD 模型 (在大鼠右側 SNc-DA 神經元中使用體內電穿孔表達αSyn致病突變體) ，在轉染後 1-6 個月後，犧牲動物收集腦脊髓液和血漿來分析循環因子的成分，如多巴胺、催產素、神經傳導物質、發炎因子、代謝物等。為了驗證PD進展的效果，我們將系統地確定引發PD 1-6個月後大鼠的行為變化，並使用免疫染色對致病性 αSyn進行全身系統的時間追踪，研究聚集的 αSyn 可能在大腦或其他器官中傳播和分佈情況。本研究成果盼能釐清致病性 αSyn在系統間傳播的潛在機制，為尋找預防 PD 進展提供有效的干預措施。 Cytosolic aggregates of the presynaptic protein α-Synuclein (αSyn) are the hallmark feature of multiple neurodegenerative diseases, including Parkinson’s disease (PD). The αSyn assembles into aggregates, depositing as Lewy bodies, causing the death of dopamine (DA) neurons in the substantia nigra pars compacta (SNc). PD is the second most common neurodegenerative disease, affecting movement control and accompanying the symptoms such as constipation, visual defects, depression, or dementia. In the past two decades, αSyn aggregation and propagation have been implicated in the pathogenesis of both familial and sporadic PD. Detection of extracellular αSyn in human cerebrospinal fluid (CSF) suggests that pathogenic αSyn may be spread via neuron-to-neuron transmission, further across brain, eyes, tears, or even intestinal neurons . These results implicate that aggregated αSyn are potentially transmitted and distributed across brain or other organs, further disrupting a variety of physiological functions. Thus, potential interventions depleting pathogenic αSyn aggregates have been long expected to dampen the transmission of pathogenic human αSyn mutants. However, to date, the fundamental mechanism underlying the transmission of the αSyn aggregates remains largely unknown, thus failing to explore the potential intervention. This subproject aims to explore how pathogenic αSyn transmission can be regulated by neural connection or circulating factors. Because most PD mouse models do not manifest SNc degeneration, a new PD rat model is required for the study of αSyn aggregation. The newly developed technique will be implemented for the study of PD progression, allowing us to trace PD progression and identify the specific biomarkers at different stages, validating PD pathogenesis and examining therapeutic agents.α-突觸核蛋白; 帕金森病; 神經傳導; 循環因子; 大鼠 PD 模型;α-Synuclein; Parkinson’s disease; Neurotransmission; Circulating factors; PD rat model