帕金森氏症是種常見的神經退化性疾病。在偶發性或家族遺傳性帕金森氏症的病 例中，Leucine-rich repeat kinase 2 (LRRK2)的突變是最常被發現的。在近期的研 究中發現到粒線體功能缺失導致氧化壓力增加與帕金森氏症中 DA 神經死亡有 關，而 LRRK2 蛋白與粒線體之功能的關係尚未明白。因此為了去探討 LRRK2 和粒線體之間與帕金森氏症的關係，我們將人類的 LRRK2 蛋白和其突變基因轉 殖在果蠅腦中 DA 相關神經裡去觀察在果蠅腦內過氧化異歧酶(SOD，主要的抗 氧化系統中的酵素)和氧化壓力。在本次的研究中，我們發現到人類 LRRK2 會增 加在粒線體裡的 SOD2 並且會去減少隨著年齡增加的氧化壓力，但其 LRRK2 G2019S 雖然也會增加 SOD2 可是其氧化壓力卻未下降。而在果蠅體內有 LRRK2 的同源基因 dLRRK，我們分析其基因失去功能的突變果蠅並觀察其 SOD 和氧化 壓力，發現到若無 dLRRK 其 SOD2 會減少並增加其氧化壓力。我們也有測試將 表現人類 LRRK2 的果蠅處理不同的環境因子去觀察其 SOD 的改變。此外，過 度磷酸化 Tau 蛋白形成堆積是帕金森氏症病患腦內常見的病理特徵並且過度磷 酸化 Tau 與氧化壓力息息相關，我們將人類 LRRK2 與人類 Tau 同時表現於果蠅 眼睛內去觀察其磷酸化 Tau 的改變。我們發現到 LRRK2 會減少 Tau 的磷酸化， 這可能代表 LRRK2 有拯救 Tau 毒性的功能。由以上結果，我們推測 LRRK2 可 能會去影響粒線體抗氧化壓力機制並扮演著一種保護的功能。

Parkinson disease (PD) is one of the most common neurodegenerative diseases. The genetic mutations in Leucine-rich repeat kinase 2 (LRRK2) have been identified as the most common cause of sporadic and familial PD. Recently, mitochondrial dysfunction has been implicated as the cause of the death of DA neurons in PD. The relationship between human LRRK2 and mitochondrial function is still unknown. Here, we express human wild-type LRRK2 and its mutant G2019S in DA neurons of Drosophila brain and characterize superoxide dismutases (SODs) which is an important mitochondrial antioxidant enzyme. We find that human wild-type LRRK2 affects the level of mitochondrial SOD2 to constrain the age-dependent increase of oxidative stress but its mutation LRRK2 G2019S does not. In contrast, in its loss of function mutants of Drosophila homolog of LRRK2, called dLRRK, we find that it decreases the level of SOD2 and increase oxidative stress. We also characterize the level of SODs in expressing LRRK2 flies under different environmental toxins. Finally, we co-express LRRK2 and Tau in fly eye system. Importantly, wild-type LRRK2 reduces the phosphorylation of Tau. Taken together, it seems that human LRRK2 plays a novel protective role to reduce mitochondrial oxidative stress.

Abstract I
中文摘要 II
Introduction 1
Materials & Methods 4
Result 7
LRRK2 regulates an age-dependent increase of the SODs in Drosophila 7
LRRK2 reduces oxidative stress in older Drosophila 8
Loss-of-function mutant, dLRRKex1/ex1 cause the decrease of SOD2 and the
increase of oxidative stress 9
LRRK2 enhances the increasing of SODs expression induced by chronic environmental toxins 9
LRRK2 decreases the phosphorylation of tau 10
Discussion 12
Figures 15
Reference 27

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