本文選題：帕金森病 + 果蠅��； 參考：《中南大學(xué)》2014年碩士論文

【摘要】：帕金森病(Parkinson's Disease, PD)是一種最常見(jiàn)的神經(jīng)退行性運(yùn)動(dòng)障礙疾病。線粒體功能損傷是PD的重要致病機(jī)制之一。目前己鑒定了16個(gè)與PD相關(guān)的基因,其中PINK1突變會(huì)導(dǎo)致常染色體隱性遺傳的PD。PINK1是一個(gè)可以錨定在線粒體上的絲氨酸/蘇氨酸激酶。大量的研究表明PINK1與線粒體的功能密切相關(guān)。PINK1缺失的果蠅表現(xiàn)為運(yùn)動(dòng)障礙及線粒體結(jié)構(gòu)和功能異常。線粒體需要通過(guò)不斷的相互融合和分裂維持其正常功能,而這一過(guò)程的紊亂會(huì)導(dǎo)致線粒體結(jié)構(gòu)和功能異常,進(jìn)一步引起細(xì)胞損傷。Drp1是線粒體分裂相關(guān)蛋白。在果蠅里進(jìn)行的遺傳互作研究表明,過(guò)表達(dá)Drp1增加線粒體的分裂可以恢復(fù)PINK1缺失導(dǎo)致的異常表型。然而Drp1恢復(fù)PINK1缺失導(dǎo)致的相關(guān)表型的具體機(jī)制還不是很清楚。我們的前期研究發(fā)現(xiàn),PINK1敲除的小鼠中Drpl596位點(diǎn)絲氨酸的磷酸化會(huì)發(fā)生改變。因此,本論文將進(jìn)一步探討Drp1S596位點(diǎn)的磷酸化對(duì)PINK1缺失果蠅的影響。 目的：探討Drp1S596位點(diǎn)的磷酸化對(duì)PINK1缺失果蠅的影響。 方法：在PINK1缺失果蠅背景下分別過(guò)表達(dá)Drp1WT, Drp1S596A(模擬去磷酸化)和Drp1S596D(模擬磷酸化),觀察Drp1S596位點(diǎn)的磷酸化對(duì)PINK1缺失導(dǎo)致的異常表型的影響。 結(jié)果：Drp1S596D和Drp1WT均可以恢復(fù)PINK1缺失果蠅的異常表型,包括翅膀姿勢(shì)異常、背部塌陷、運(yùn)動(dòng)能力下降、肌肉和多巴胺能神經(jīng)元線粒體形態(tài)異常以及ATP生成減少；而Drp1S596A不能使PINK1缺失果蠅的運(yùn)動(dòng)能力及肌肉和多巴胺能神經(jīng)元中的線粒體形態(tài)恢復(fù)正常,但是Drp1S596A也能使翅膀異常、ATP生成水平恢復(fù)正常。 結(jié)論：Drp1可能通過(guò)S596位點(diǎn)的磷酸化來(lái)參與調(diào)節(jié)PINK1介導(dǎo)的線粒體的形態(tài)和功能。這為闡明Drp1恢復(fù)PINK1缺失果蠅異常表型的具體機(jī)制,進(jìn)一步了解PD的發(fā)病機(jī)制提供了實(shí)驗(yàn)依據(jù)。
[Abstract]:Parkinson's disease (PD) is one of the most common neurodegenerative motor disorders. Mitochondrial dysfunction is one of the important pathogenetic mechanisms of PD. Sixteen PD-related genes have been identified, of which PINK1 mutation leads to autosomal recessive inheritance of PD.PINK1, a serine / threonine kinase anchored on mitochondria. A large number of studies have shown that Drosophila melanogaster, which is closely related to the function of mitochondria and the deletion of PINK1, shows dyskinesia and abnormal structure and function of mitochondria. Mitochondria need to maintain their normal function through continuous fusion and division, and the disorder of this process will lead to abnormal structure and function of mitochondria, and further cause cell damage. Drp1 is a mitosynthesis-related protein of mitochondria. Genetic interaction studies in Drosophila have shown that overexpression of Drp1 increases mitochondrial division and restores abnormal phenotypes caused by PINK1 deletion. However, the specific mechanism of Drp1 recovery of the associated phenotypes resulting from PINK1 deletion is not well understood. Our previous study found that Drpl596 site serine phosphorylation changes in PINK1 knockout mice. Therefore, the effect of phosphorylation of Drp1S596 site on PINK1 deletion in Drosophila melanogaster is further investigated. Objective: to investigate the effect of phosphorylation of Drp1S596 site on PINK1 deletion in Drosophila melanogaster. Methods: Drp1WT, Drp1S596A (simulated dephosphorylation) and Drp1S596D (simulated phosphorylation) were overexpressed under the background of PINK1 deletion in Drosophila melanogaster respectively. The effects of phosphorylation of Drp1S596 site on abnormal phenotypes induced by PINK1 deletion were observed. Results both 1 / Drp1S596D and Drp1WT could restore the abnormal phenotypes of Drosophila PINK1 deletion, including abnormal wing posture, back collapse, decreased motor ability, abnormal mitochondrial morphology of muscle and dopaminergic neurons, and decreased ATP production. However, Drp1S596A could not restore the motor ability of Drosophila melanogaster PINK1 deficiency and mitochondrial morphology in muscle and dopaminergic neurons, but Drp1S596A could also restore the level of ATP production in abnormal wings of Drosophila melanogaster. Conclusion it is suggested that the phosphorylation of S596 site may be involved in regulating the morphology and function of mitochondria mediated by PINK1. This provides experimental evidence for elucidating the specific mechanism of Drp1 restoring the abnormal phenotype of PINK1 deletion Drosophila and further understanding the pathogenesis of PD.
【學(xué)位授予單位】：中南大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2014
【分類(lèi)號(hào)】：R742.5

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