系統識別號 U0026-2808201813555200
論文名稱(中文) 探討WWOX和Parkin在調節神經元死亡中的角色
論文名稱(英文) Potential role of WWOX and Parkin in regulating neuronal death
校院名稱 成功大學
系所名稱(中) 分子醫學研究所
系所名稱(英) Institute of Molecular Medicine
學年度 106
學期 2
出版年 107
研究生(中文) 李依庭
研究生(英文) I-Ting Lee
學號 T16051066
學位類別 碩士
語文別 英文
論文頁數 74頁
口試委員 指導教授-張南山
中文關鍵字 腫瘤抑制蛋白雙色胺酸結構域氧化還原酶 (WWOX/ WOX1/FOR)  帕金森氏症  神經元死亡  神經退化性疾病  帕金 (Parkin)  1-甲基-4-苯基-1,2,3,6-四氫吡啶 (MPTP)  1-甲基-4-苯基吡啶 (MPP+)  蛋白質交互作用 
英文關鍵字 WW Domain-Containing Oxidoreductase (WWOX)  Parkinson’s disease (PD)  neuronal death  neurodegenerative disease  Parkin  MPTP  MPP+  Protein–protein interactions 
中文摘要 臨床病例顯示,WWOX基因的改變會導致嚴重的神經疾病,例如:運動失調,癲癇發作,癡呆,生長遲緩和神經退化性病變。WWOX在緩解阿茲海默症中扮演著關鍵性的角色。在帕金森氏症的疾病動物模型中,當大鼠接受神經毒素1-甲基-4-苯基吡啶(MPP +)刺激時,在凋亡神經元中Tyr33磷酸化的WWOX (pY33-WWOX)表現量會上調。然而,即使己知這些現象,WWOX在帕金森氏疾病中的作用尚不明朗。首先,透過酵母菌雙雜合系統、螢光共振能量轉移分析,證明WWOX的可以與帕金森症相關蛋白Parkin結合。螢光共振能量轉移分析還顯示Y33R-WWOX突變體和顯性失活的WWOX消除了與Parkin的結合作用,表明了Parkin主要與pY33-WWOX結合。通過cell cycle分析,在SK-N-SH神經母細胞瘤中瞬時過量表達WWOX和Parkin會誘導加成細胞凋亡的作用。細胞在MPP+刺激後, Parkin和pY33-WWOX皆上調; WWOX/Parkin複合物的結合在MPP+刺激後有被增加,這些結果支持該複合物可能導致神經元死亡,而雌激素17 -雌二醇(E2)卻可以解離MPP+增強的複合物形成。而在免疫細胞化學螢光顯微鏡中也觀察到類似的結果。最後,我們利用1-甲基-4-苯基-1,2,3,6-四氫吡啶(MPTP)在Wwox野生型和異型小鼠中建立帕金森氏症模型。Wwox異型小鼠能夠減弱腦黑質中多巴胺神經元的損失,指出高表現量的WWOX有利於PD的發展。總合來說,我們發現了帕金森氏症的發病機制中,有 WWOX / Parkin此複合物參與調節的新機制。E2抑制了因MPP+刺激而增加的WWOX / Parkin複合物,可能是因為E2在MPP+造成的神經元死亡的訊息傳導中發揮了其神經保護的作用。
英文摘要 Clinical cases have shown that WWOX gene alterations cause severe neural diseases, such as the ataxia, seizures, dementia, growth retardation and neurodegeneration. WWOX also plays a critical role in the progression of Alzheimer’s disease (AD). In the Parkinson disease (PD) model, Tyr33 phosphorylation of WWOX (pY33-WWOX) is upregulated in apoptotic neurons when rat was exposed with neurotoxin 1-methyl-4-phenylpyridinium (MPP+). However, the role of WWOX in PD remains unclear. PD-associated protein, Parkin, its interaction with WWOX is determined by yeast two hybrid system, Förster resonance energy transfer (FRET) analysis. FRET analysis also showed that Y33R-WWOX mutant and dominant negative WWOX abrogates the interaction with Parkin, revealing that Parkin mainly interacts with pY33-WWOX. By cell cycle analysis, transiently overexpressed WWOX and Parkin in SK-N-SH neuroblastoma induce apoptosis in an additive manner. Cellular exposure to MPP+ significantly induces the up-regulation of Parkin and pY33-WWOX; the binding affinity of WWOX/Parkin complex is enhanced after MPP+ treatment, supporting that the complex may cause neuronal death, whereas 17-estradiol (E2) can dissociate the MPP+-enhanced complex formation. Finally, we use MPTP model of PD in Wwox wild type and heterozygous mice. The Wwox heterozygous mice attenuate the dopaminergic neuron loss in substatia nigra, indicating that the high level of WWOX contributes to the development of PD. Together, we discover a novel mechanism for the pathogenesis of PD, which is involved WWOX/Parkin complex. E2 blocks the increasing formation of WWOX/Parkin complex, suggesting that the neuroprotective effect of E2 acts in MPP+-induced neuronal death.
論文目次 中文摘要 I
Abstract II
誌謝 III
Figure Index VI
Abbreviations VII
Introduction 1
Goal of this study 1
WW Domain-Containing Oxidoreductase (WWOX) 1
WWOX phosphorylation and cell death signaling 3
WWOX gene expression in the brain 4
WWOX in neurological development 4
WWOX in neuronal death, Alzheimer’s disease (AD) and Parkinson disease (PD) 5
Neuronal death and neurodegeneration 7
Parkinson’s disease (PD) 8
Spreading pathology 8
Parkin (PARK2) 10
Estrogen in neuroprotection 11
Estrogen receptors (ERs) 12
E2 and E2/ERs signaling 13
Estrogen and WWOX 13
Materials and Methods 15
Cell culture 15
cDNA expression construct and transient gene expression 15
Antibodies 15
Cytotrap yeast two-hybrid analysis 16
Cell cycle Analysis 16
Animals and treatment 17
Immunohistochemistry (IHC) 17
Sodium dodecyl sulfate (SDS)-polyacrylamide gels electrophoresis (PAGE) and Western blot 17
Förster resonance energy transfer (FRET) 18
Time lapse tri-molecular FRET microscope 19
Rotarod test 19
MTT assay 19
Statistical analysis 19
Results 21
The WW Domains of WWOX binds Parkin 21
Transiently overexpressed WW domain of WWOX and Parkin induces apoptosis 21
Neurotoxin MPP+ increases expression of pY33-WWOX and Parkin 23
Neurotoxin MPP+ enhanced the binding affinity of WWOX and Parkin 23
17b-estradiol (E2) blocks the MPP+-enhanced the formation of WWOX/Parkin complex 24
Wwox heterozygous mice attenuates SN DA neurons death in the MPTP-induced mouse model of Parkinson disease 25
Discussion 28
Conclusion 33
References 34
Figure 45
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