2016-08-012024-05-17https://scholars.lib.ntu.edu.tw/handle/123456789/692116摘要：多重系統退化症（MSA）是一種罕見但致命的神經退化性疾病，臨床上表現非典型的巴金森症，動作緩慢，平衡失調，小腦萎縮，自主神經系統障礙。其病理特徵為alpha-synuclein 沉積於寡突膠細胞中。由於alpha-synuclein 被發現具有自我繁殖、傳播及重建的能力，MSA 因此也被認為屬於prion-like 疾病，但機轉尚不明瞭。已知alpha-synuclein 與脂筏皆參與細胞內外的囊泡運輸，且脂筏與許多脂質運輸蛋白可能參與alpha-synuclein 在寡突膠細胞內的沉積。此外，anti-GAD 或anti-TPO 抗體、脊髓小腦性共濟失調亞型及與調節粒線體呼吸傳遞鏈有關的COQ2 基因多型性等病因都有可能表現多重系統退化症。因此本研究的目的：（1）建立第一個台灣多重系統退性症的資料庫，包括流行病學、臨床、血清及基因組織，藉以分析環境、血清生化、基因等可能與疾病發生之相關性因子。（2）建立寡突膠細胞的初代細胞模式，藉以探討脂筏、脂質運輸蛋白、膽固醇代謝與alpha-synuclein 在神經元與寡突膠細胞擴散以及沉積的病理機轉。（3）建立基因轉殖小鼠的模式，觀察動物行為及組織變化，尋找治療標靶以阻止疾病的進展。本研究結果也可作為其他alpha-synuclein 沉積的退化性疾病，如巴金森症與路易體失智症新藥開發的試驗模式。<br> Abstract: Multiple system atrophy (MSA), is a rare yet fatal neurodegenerative disease characterized byalpha-synuclein deposition in “oligodendrocyte＂. Recently, it is recognized as a human prion-likedisease because of the capability of self-reconstruction and self-propogation of the alpha-synucleinwith unknown mechanism. Alpha-synuclein and lipid raft are well-known to their role inintracellular or extracellular vesicle transportation. Lipid raft and neumerous lipid transporters alsoparticipate in neurogenesis and neuroinflammation in various neurodegenerative disorders includingHuntington disease or Alzheimer＇s disease. Besides, several etiologies mimic MSAphenomenology including autoimmune disorders associated with anti-GAD or anti-TPO antibodies,spinocerebellar ataxia (SCA) subtypes and COQ2 gene polymorphism involving in mitochondrialrespiratory chain regulation. Whether manipulation of lipid raft can reverse the early finding ofmyelin protein redistribution, block alpha-synuclein transmission from neurons to oligodendrocytes,postpone the demyelination and subsequent cell death of oligodendrocyte, alleviateautoantibody-induced neuroinflammation in early MSA deserves further investigation. To answerthe questions, we plan to construct the first thorough Taiwanese MSA patient bank to analyze theenvironmental, genetic and serobiochemical factors on the development and progression of MSA;focus on cell-cell interaction between neurons, astrocytes and oligodendrocytes; aim at interactionbetween lipid raft, lipid transporters such as P25α, cholesterol metabolsim and alpha-synuclein invivo and in vitro; in order to decode the mechanism of spreading of alpha-synucleinopathy and seekthe potential therapeutic target to block and discontinue the lethal progressive proteinopathy ofneurodegenerative diseases in MSA . The findings may translate to other alpha-synucleinopathy,such as Parkinson＇s disease, diffused lewy body dementia.多重系統退化症寡突膠細胞脂筏alpha-synucleinp25αmultiple system atrophyoligodendrocytelipid raftalpha-synucleinP25α