2017-01-012024-05-13https://scholars.lib.ntu.edu.tw/handle/123456789/654751摘要：帕金森病（PD）是第二大常見的神經退化性疾病，主要影響運動控制。帕金森病的主要病因被認為是黑質中多巴胺神經元的死亡，但是什麼是選擇性地導致多巴胺神經元變脆弱的原因仍是未解之謎。在過去二十年中，發現α-突觸核蛋白聚集和粒線體功能障礙是家族性和散發性帕金森病的發病機制。然而，α-突觸核蛋白會在健康的許多神經元類型中普遍表達，例如黑質，皮質，海馬，丘腦和小腦。此外，帕金森病中的α-突觸核蛋白聚集可以從神經元擴散到神經元，使路易體在腦中的蔓延分佈。這些結果表明帕金森病是由聚集的α-突觸核蛋白中斷多巴胺神經元中的獨特功能而引起的。為了解為什麼α-突觸核蛋白聚集主要會損害多巴胺神經元，我們使用兩種系統生物學方法（包括蛋白質組學和代謝組學）來探索多巴胺神經元和非多巴胺神經元之間的功能差異。藉此，我們可開發新的動物模型來驗證帕金森病的因果關係，跟&#36394;帕金森病進展，調查疾病的分子機制，並測試治療相關藥物的作用。由於許多神經退化性疾病是由於蛋白質聚集不良所造成的，因此在不久的將來，這種藥物的發現可以擴展到其他神經退化性疾病。在帕金森病中率先開展的研究，最終可更廣泛地為神經退化性疾病產生成功的治療方向。<br> Abstract: Parkinson`s disease (PD) is the second most common neurodegenerative disease, affecting movement control. The primary cause for PD symptoms has been recognized as the death of dopamine (DA) neurons in substantia nigra, but what selectively causes DA neurons the most vulnerable remains mysterious. In past two decades, α-synuclein aggregation and mitochrondrial dysfunction are implicated in the pathogenesis of both familial and sporadic PD. However, α-synuclein is ubiquitously expressed in many neuronal types in health, such as substantia nigra, cortex, hippocampus, thalamus, and cerebellum. Moreover, α-synuclein aggregation in PD can spread from neuron to neuron, exhibiting the distribution of Lewy bodies across brain. These results implicate that PD is caused by aggregated α-synuclein interacting with and further interrupting the function of a unique set of partners that are preferentially required for DA neurons. To understand why α-synuclein aggregation primarily damages DA neurons, we aim to explore the functional differences between DA neurons and non-DA neurons by using two systems biology approaches, including proteomics and metabolomics. Thus, we can develop this new animal model to validate the PD causality, trace PD progression, investigate disease mechanisms, and test the effects of therapeutic agents. Since many neurodegenerative diseases are due to defective protein aggregation, the findings in this grant may be extended to other neurodegenerative diseases in the near future. Approached being pioneered in PD research may ultimately yield successful treatments for a broader range of neurodegenerative diseases.帕金森病多巴胺神經元α-突觸核蛋白蛋白質組學代謝組學Parkinson`s diseasedopamine neuronsα-synucleinproteomicsmetabolomics