帕金森氏症是一種常見發生於老年人的神經退化性疾病，可分為遺傳性與突發性的帕金森氏症。帕金森氏症主要有兩個特有的病徵，其一為位於黑質緻密區的分泌多巴胺的神經細胞逐漸死亡，另一個病徵則為在細胞質中形成路易氏體。除此之外，在帕金森氏症中粒線體也會失去其正常生理功能。在遺傳性的帕金森氏症中，α-突觸核蛋白的突變扮演很重要的角色，並且α-突觸核蛋白是路易氏體重要組成物。α-突觸核蛋白與遺傳性的帕金森氏症息息相關，然而，前研究中帶有點突變的α-突觸核蛋白的基因轉殖鼠病無法模擬與病人類似的病徵。因此我們假設帶有不同的多重點突變的α-突觸核蛋白基因轉殖鼠更可以模擬病人所產生的病徵。首先我們將正常的α-突觸核蛋白基因、帶有點突變(A53T)的α-突觸核蛋白基因、帶有兩個點突變(A53T/A30P與A53T/E46K)的α-突觸核蛋白基因及帶有三個點突變(A53T/A30P/E46K)α-突觸核蛋白基因送入神經瘤母細胞株內，發現帶有三個點突變α-突觸核蛋白基因可產生較多的α-突觸核蛋白與造成較高的細胞株死亡率，並且會造成較多粒線體分裂的趨勢。然而，卻對由瘤母細胞分化而成的分泌多巴胺的神經細胞並未產生影響。為了證實在細胞株中得到的結果，我們產生了帶有兩個點突變(A53T/E46K)及三個點突變(A53T/A30P/E46K)的α-突觸核蛋白基因轉殖鼠，在三個點突變的α-突觸核蛋白基因轉殖鼠5.5個月時發現在其大腦皮層中有產生α-突觸核蛋白堆積的現象；而帶有兩個點突變的α-突觸核蛋白基因轉殖鼠在3個月時並無產生-突觸核蛋白堆積的現象。除此之外，這兩種老鼠在三個月前並無產生疾病相關的症狀。綜合以上的結果可得知，探討由突變的α-突觸核蛋白所造成的影響將有助於對帕金森氏症有更進一步的了解。

Summary
Parkinson’s disease (PD) is one of the most common neurodegenerative diseases,. The main characteristics of PD are progressive degeneration of dopaminergic neurons in the substantia nigra pars compacta(SNpc) and formation of inclusions called Lewy bodies. In familial PD, alpha-synuclein(α-syn) gene is one of mutant genes, and it is the main component of Lewy bodies. α-syn highly correlated with familial PD, however, there are no animal model carrying mutant α-syn could be consistent to Parkinson disease patients. Therefore we hypothesized that different multiple mutations within α-syn gene might provide better model in PD. First, we analyzed the expression of alpha-synuclein after overexpressing the mutant alpha-synuclein genes, and found double mutations (A53T/E46K) and triple mutations (A53T/A30P/E46K) could express more alpha-synuclein in 293FT and N2a cells in vitro. We also observed lower cell viability and higher apoptotic marker in vitro after overexpressing triple mutations (A53T/A30P/E46K) α-syn. In order to confirm the above results in vivo, we generated double mutations (A53T/E46K) and triple mutations (A53T/A30P/E46K) transgenic mice. We found α-syn formed aggregates in cortex in triple mutations (A53T/A30P/E46K) transgenic mice at 5.5 months of age. However, we could not observe formation ofα-syn aggregates in double mutations (A53T/E46K) at 3 months of age. Additionally, these transgenic mice did not show motor dysfunction until 3 month of age. Taken together, understanding the information of α-syn-mediated effects could provide further insight for PD.
Abstract
Parkinson’s disease (PD) is one of the most common neurodegenerative diseases, including sporadic and familial types. The main characteristics of PD are progressive degeneration of dopaminergic neurons in the substantia nigra pars compacta(SNpc) and formation of inclusions called Lewy bodies. Additionally, mitochondria dysfunction is an important alteration in PD. In familial PD, alpha-synuclein(α-syn) gene is one of mutant genes, and it is the main component of Lewy bodies. α-syn highly correlated with familial PD, however, there are no animal model carrying mutant α-syn could be consistent to Parkinson disease patients. Therefore we hypothesized that different multiple mutations within α-syn gene might provide better model in PD. First, we analyzed the expression of alpha-synuclein after overexpressing the mutant alpha-synuclein genes, and found double mutations (A53T/E46K) and triple mutations (A53T/A30P/E46K) could express more alpha-synuclein in 293FT and N2a cells in vitro. We also observed lower cell viability and higher apoptotic marker in vitro after overexpressing triple mutations (A53T/A30P/E46K) α-syn. Furthermore, triple mutations (A53T/A30P/E46K) α-syn could lead abnormal mitochondria morphology. However, overexpressing mutant α-syn could not affect tyrosine hydroxylase neurons. In order to confirm the above results in vivo, we generated double mutations (A53T/E46K) and triple mutations (A53T/A30P/E46K) transgenic mice. We found α-syn formed aggregates in cortex in triple mutations (A53T/A30P/E46K) transgenic mice at 5.5 months of age. However, we could not observe formation ofα-syn aggregates in double mutations (A53T/E46K) at 3 months of age. Additionally, these transgenic mice did not show motor dysfunction until 3 month of age. Taken together, understanding the information of α-syn-mediated effects could provide further insight for PD.

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