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研究生: 葉柏安
Po-An Yeh
論文名稱: 研究果蠅PP2A B次單元twins的功能以及和Tau蛋白的交互作用
Functional Study of twins, the Drosophila PP2A B Subunit and it’s Interaction with Tau
指導教授: 蘇銘燦
Su, Ming-Tsan
學位類別: 博士
Doctor
系所名稱: 生命科學系
Department of Life Science
論文出版年: 2010
畢業學年度: 98
語文別: 英文
論文頁數: 119
中文關鍵詞: 阿茲海默症神經退化疾病小腦萎縮症
論文種類: 學術論文
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  • PR55Bbeta的表現異常,長久以來一直被認為是小腦萎縮12型的致病原因。隨後的研究指出,PR55Bbeta的表現量增加,極可能是小腦萎縮12型的致病原因。然而,可以模擬小腦萎縮12型的動物模式,一直沒被建立,以其在生物體內的致病機轉仍不明確。在本研究實驗中,PR55Bbeta過渡表現的果蠅模式被建立,而且其果蠅表現出運動力下降和神經病變的特徵。在研究PR55Bbeta和Tau蛋白之間的作用時,我意外的利用果蠅背甲上毛的數目,建立一個新穎的模式系統,可以穩定的檢測出Tau蛋白的磷酸化程度。研究期間,我更發現,磷酸化的Tau蛋白,有保護神經的功能,並且延長果蠅的壽命。相反的,無法磷酸的Tau蛋白,對神經的發育有不好的影響。最後,本研究也指出,PP2A的B次單元與細胞骨架的調控有關,為一個新發現的嶄新的功能。也許這些研究成果,可以連結小腦萎縮12型和阿茲海默症之間致病機轉的關連。

    Misregulated PR55Bβ, a B regulatory subunit of protein phosphotase 2A (PP2A), has long been documented to be associated with spinocerebellar ataxia type 12 (SCA12). Mounting evidence has shown that overexpression of PR55Bβ might be the plausible cause of SCA12. However, the pathogenic animal model of SCA12 remains absent and needs to be established to underline its pathomechanism in vivo. In this study, it has been shown that overexpression of PR55Bβ in flies led to severely retarded locomotion activity and aberrant neuronal morphology. During the investigation of the genetic interaction between PR55Bβ and Tau, I hit upon a novel notum assay system for robustly assessing phosphorylation of Tau. Further investigations revealed that hyperphosphorylated Tau might protect and somehow benefit the adult aging flies resulting in longer life-span. Conversely, both hypophosphorylated Tau and overexpression of PR55Bβ exerted detrimental effects on the dendritic outgrowth and resulted in slow locomotion activity and shortened life-span. Finally, I demonstrated that actin polymerization is positively regulated by Drosophila PP2A-B subunit, opening a new frontier for the role played of PP2A in the regulation of actin cytoskeleton. These studies might provide a link between the pathogenesis of Alzheimer’s disease and SCA12.

    Introduction Expansion of a CAG trinucleotide repeat in the 5´ region of PPP2R2B is associated with SCA12 ----------------------------------------------------------- 1 The components of PP2A ------------------------------------------------------------ 2 The PP2A inhibitors and activator -------------------------------------------------- 5 Identified functions of twins in Drosophila and other regulatory subunits in other species ------------------------------------------------------------------------ 5 PP2A is the pivotal phosphatase of Tau concerned with Alzheimer’s disease 7 The controversial role of hyperphosphorylated Tau ------------------------------ 9 The involvement of PP2A in tumorgenesis and apoptosis ----------------------- 10 The regulation of actin cytoskeleton by PP2A 12 Materials and Methods Fly strains and stocks ----------------------------------------------------------------- 13 Molecular cloning and generation of transgenic flies ---------------------------- 14 Scanning electron microscopy ------------------------------------------------------- 15 Immunoblotting ------------------------------------------------------------------------ 15 Lithium chloride and alsterpaullone treatment ------------------------------------ 16 RT-PCR --------------------------------------------------------------------------------- 17 Notum bristle quantification --------------------------------------------------------- 18 LacZ staining --------------------------------------------------------------------------- 18 Clonal expression in salivary gland and immunofluorescence ------------------ 18 Life span measurement --------------------------------------------------------------- 19 Climbing assay ------------------------------------------------------------------------- 20 SH-SY5Y cells culture ---------------------------------------------------------------- 20 Results PP2A-B expression pattern in the fly nervous system ---------------------------- 21 The detrimental effects of PP2A-B overexpression on the fly nervous system 22 PP2A-B dephosphorylates human tau protein in vivo ---------------------------- 23 PR55Bβ2 did not appear to rescue hTauWT inducing rough eye phenotype --- 24 Notum bristle number is reduced by hTau expression and subsequently recovered by co-expressing PP2A-B ------------------------------------------- 25 Bristle loss caused by hTau overexpression is phosphorylation-dependent -- 27 Attenuating GSK3β activity decreases hTau phosphorylation and rescues hyperphosphorylated hTau inducing notum bristle loss ---------------------- 29 Heterozygous depletion of endogenous Tau restores bristle loss on hTau expressing notum ------------------------------------------------------------------ 31 Usefulness as a drug screening method for tau protein phosphorylation modulators -------------------------------------------------------------------------- 31 Expression of disease associated hTau elicits axonal dilation phenotype ------ 33 Early expression of hyperphosphorylated Tau inhibits neuronal cell fate differentiation ---------------------------------------------------------------------- 35 Phosphorylation of hTau elongates fly life-span ---------------------------------- 35 Expression of hypophosphorylated hTauAP impaired neuronal development - 37 Neuronal expression of PP2A-B reduced dendritic complexity and shortened life-span of flies -------------------------------------------------------------------- 38 Overexpression of PP2A-B sustained cell apoptosis ----------------------------- 39 Knockdown of twins expression inhibited cell apoptosis ------------------------ 41 twins plays a role in promoting actin polymerization ---------------------------- 42 Overexpression of twins elicits phosphorylation of Cofilin, Ezrin and Myosin ------------------------------------------------------------------------------ 42 Depletion of twins retarded photoreceptor soma migration --------------------- 43 Discussion B regulatory subunits specify PP2A activity toward Tau in vivo ---------------- 45 Notum bristle loss phenotype is specified to Tau phosphorylation, rather than other neurotoxic proteins --------------------------------------------------- 45 The notum bristle assay system for assessment of Tau phosphorylation can be applied in pharmaceutical test ------------------------------------------------ 47 The limitation of the Tau expressing notum system ------------------------------ 47 ddaC nervous system can serve as an assay tool for assessing neurotoxic effect --------------------------------------------------------------------------------- 48 Hyperphosphorylated Tau might be neuroprotective and beneficial to adult fly nervous system ----------------------------------------------------------------- 49 Hyperphosphorylation of Tau is an adaptive response for nervous systems during inhospitable conditions --------------------------------------------------- 51 Overexpression of PR55Bβ2 over-dephosphorylating Tau might be one of the insults of SCA12 pathogenesis ---------------------------------------------- 52 Overexpression of PP2A-B potentially triggers apoptosis in vivo -------------- 53 Conclusion --------------------------------------------------------------------------------- 55 Reference ---------------------------------------------------------------------------------- 57 Figures and Legends Figure 1. twins expresses in the nervous system and functions equally to a human B subunit, PR55Bβ2. ----------------------------------------------------- 85 Figure 2. Overexpression of PR55Bβ2 with pan-neuronal driver shortens fly life-span. ---------------------------------------------------------------------------- 87 Figure 3. B subunits of PP2A dephosphorylated human tau protein in vivo. - 88 Figure 4. PR55Bβ2 did not show distinguishable rescue in traditional eye model with GMR-Gal4 driver. --------------------------------------------------- 90 Figure 5. Fly notum bristle number was diminished by hyperphosphorylated hTau expression and recovered by co-expressing B subunits of PP2A. ---- 91 Figure 6. GMR-GAL4 expression of only widerborst (WDB) shows severe rough eye phenotype. ------------------------------------------------------------- 93 Figure 7. Bristle loss caused by hTau expression is phosphorylation-dependent. ------------------------------------------------------ 94 Figure 8. Expression dosage analysis of fly stains carrying hTau variants constructs. --------------------------------------------------------------------------- 96 Figure 9. Eye phenotypes of hTau variants. ---------------------------------------- 97 Figure 10. Dominant negative GSK3β recovered bristle loss and attenuated hTau phosphorylation. ------------------------------------------------------------- 98 Figure 11. Heterozygously depletion of endogenous sgg also showed significant rescue of bristle loss on hTau expressing notum. ---------------- 100 Figure 12. Heterozygously depletion of endogenous Tau restored the bristle number on hTau expressing notum. --------------------------------------------- 102 Figure 13. Feeding with lithium chloride strongly inhibits phosphorylation of hTau but leads to toxicity for fly survival. ---------------------------------- 103 Figure 14. A more selective GSK3β inhibitor, alsterpaullone, rescued nota bristle loss on hTauWT expressing nota and elongated the life span of hTauR406W expressing flies. ------------------------------------------------------- 104 Figure 15. Expressions of disease associated hTau mutants lead to aberrant axon dilation in md-da neurons of the third instar larva. --------------------- 106 Figure 16. Aberrant axonal dilation induced by hTau expression is associated with twins. -------------------------------------------------------------------------- 107 Figure 17. Early expression of pseudophosphorylated hTauE14 inhibits neuronal cell fate differentiation. ------------------------------------------------ 108 Figure 18. Phosphorylation of Tau elongated fly life-span. ---------------------- 109 Figure 19. Expression of phosphorylation-incompetent hTauAP retarded dendritic outgrowth. --------------------------------------------------------------- 110 Figure 20. Neuronal expression of PR55Bβ2 reduced dendritic complexity and shortened life-span of flies. -------------------------------------------------- 111 Figure 21. Overexpression of PP2A-B promotes cell apoptosis in vivo. ------ 112 Figure 22. Depletion the expression of twins inhibits cell apoptosis resulting in accessing survival cells. ------------------------------------------------------- 114 Figure 23. twins positively regulates actin polymerization. --------------------- 116 Figure 24. Overexpression of twins elevated phosphorylation of polymerized-actin relevant proteins. -------------------------------------------- 117 Figure 25. twins is essential for photoreceptor soma migration. ---------------- 118 Figure 26. acu rescued malformed rhabdomere causing by twins overexpression. --------------------------------------------------------------------- 119

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