帕金森氏症是一種主要影響運動的發展性神經系統疾病，發病年齡通常在65歲以上，另外，也有部分患者的發病年齡在20到40歲，稱為青年型帕金森氏症，這些患者大多是因為先天性基因異常、遺傳基因異常造成較早發病。在遺傳的因素中，目前已有多個研究證實許多基因突變是導致帕金森氏症的原因之一。而其中CHCHD2為穩定粒線體代謝的重要蛋白質，對於調節粒線體的電子傳遞鏈和活性含氧物扮演重要的角色，CHCHD2的突變和缺失在許多患者中已被發現，除此之外，在許多神經退化性疾病中，Tau蛋白的不正常磷酸化會造成Tau蛋白堆積在細胞內，進而造成神經細胞凋亡。在此研究中，我們利用果蠅作為模式生物來探討CHCHD2和Tau表現在多巴胺神經元中會對粒線體的氧化壓力造成什麼影響。結果發現過量表現Tau不只會增加粒線體的氧化壓力，也會使得爬行能力下降，但同時表現CHCHD2時則可以有效的降低氧化壓力以及提升爬行能力，在果蠅的視覺系統中，表現CHHCD2也能回復Tau所造成的不規則排列的複眼細胞。因此，我們的研究證實了過量表現CHCHD2在許多病理機制裡扮演了保護的角色，對日後在生物中研究帕金森氏症的致病機轉可能有所貢獻。

Parkinson’s disease (PD) is a progressive disorder of the central nervous system that primary affects movements. The age of disease onset is usually 65 years or older. The age of young onset Parkinson’s disease (YOPD) is between 20 to 40 years old. These early onset patients are often due to congenital genetic abnormalities and hereditary genetic abnormalities. In genetic factors, many studies have confirmed that the genes mutation may lead to PD. One of the genes in human is CHCHD2 which plays an important role in the regulation of electron transport chain and the level of reactive oxygen species. Genetic mutation and deletion in CHCHD2 are found in some patients with PD. In addition, the abnormal phosphorylation of tau causes tau protein aggregate in the cytosol, and lead to neuron death in many neurodegenerative diseases. In this study, we use Drosophila as a model to investigate how CHCHD2 and Tau affect mitochondrial oxidative stress in the dopaminergic neurons. Our results showed that overexpression of tau increased the mitochondrial oxidative stress and decreased the motor ability. Co-expression of CHCHD2 can effectively rescue the defect. In the visual system, the disorganized eye arrangement also rescued by overexpression of CHCHD2. As such, our results provide evidences that overexpression of CHCHD2 have a protective function in many aspects.

摘要 Ⅰ
Abstract ⅠⅠ
Acknowledgement ⅠⅠⅠ
Contents V
Introduction 1
1.Parkinson's disease 1
2.Symptoms of Parkinson’s disease 2
3.Pathology of Parkinson’s disease 3
4.Coiled-coil-helix-coiled-coil-helix domain containing 2(CHCHD2) 4
5.CHCHD2 family and function 5
6.CHCHD2 mutations 6
7.Microtubule-associated protein Tau (MAPT) 7
8.Tau phosphorylation 8
9.The pathological effects of tau phosphorylation 8
Materials and Methods 11
1.Drosophila stocks and culture 11
2.Brain dissection and confocal images 11
3.Scanning electron microscope (SEM) 12
4.Locomotor assay 12
5.Statistical analysis 13
Results 14
The human CHCHD2 mainly localizes to the mitochondria in the Drosophila adult brain. 14
Overexpression of the CHCHD2 rescue the defective mitochondria caused by human wild type tau4 in dopaminergic neurons. 15
Overexpression of the CHCHD2 rescue the locomotor ability caused by human wild type tau4. 17
Overexpression of the CHCHD2 rescue the eyes phenotype caused by human wild type tau4. 18
Discussion 20
CHCHD2 shows a protective effect on mitochondria function. 20
The variation level of CHCHD2 in different stress. 21
CHCHD2 connects mitochondrial apoptosis to cancer. 22
Figures 23
Figure 1. The sequence alignment of human CHCHD2 was injected into the Drosophila eggs. 23
Figure 2. The human CHCHD2 overlaps the mitochondrial signal expressing in the dopaminergic neurons of male Drosophila adult brains. 24
Figure 3. The overlap signal of human CHCHD2 and the mitochondrial expressing in the dopaminergic neurons of female Drosophila adult brains. 26
Figure 4. Expression of human CHCHD2 in the dopaminergic neurons reduce mito-timer signal in week1 fly’s brain. 28
Figure 5. Expression of human CHCHD2 in the dopaminergic neurons reduce mito-timer signal in week5 fly’s brain. 30
Figure 6. The locomotor ability of flies expressing human CHCHD2 and human wild type tau4 in the dopaminergic neurons with different age. 32
Figure 7. The eyes morphology displayed in human CHCHD2 and gl-tau group and separated by sex. 33
References 34

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