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題名 大鼠紋狀體腦區 CK2/DARPP-32/GAD67 蛋白細胞訊息傳遞路徑對神經傳遞物質和運動行為影響之探討
The influence of striatal CK2/DARPP-32/GAD67 signaling pathway on neurotransmitter and motor behavior of rats
作者 黃鉉豐
Huang, Xuan Feng
貢獻者 趙知章
Chao, Chi Chang
黃鉉豐
Huang, Xuan Feng
關鍵詞 紋狀體
MSN 細胞
蛋白激酶 CK2
DARPP-32 蛋白
麩胺酸脫羧酵素-67
酪胺酸羥化酶
多巴胺
-丁氨基酪酸
striatum
medium spiny GABAergic neurons
protein kinase CK2
DARPP-32
Glutamic acid decarboxylase 67
-aminobutyric acid
dopamine
Tyrosine Hydroxylase
日期 2016
上傳時間 1-三月-2016 10:41:29 (UTC+8)
摘要 蛋白激酶 CK2 是一種針對受質蛋白之絲胺酸/蘇胺酸進行磷酸化之多種功能的蛋白激酶，參與調節包括神經可塑性和神經保護等許多神經系統的功能，但是其分子層面的細胞機制目前尚未完全釐清。研究發現CK2在紋狀體腦區的表現量與活性皆高於其他腦區，而紋狀體之中型多刺狀GABA 神經元（medium spiny neuron, MSN）中DARPP-32 (Dopamine- and cAMP-regulated phosphoprotein, Mr 32 kDa) 蛋白的Ser102胺基酸被證實是 CK2 的磷酸化作用位置。許多研究文獻證實在多巴胺訊息傳遞路徑中， DARPP-32 蛋白之 Ser34/Thr75 的磷酸化現象參與藥物成癮相關生理行為的作用，然而 Ser102 的磷酸化作用與 MSN 細胞對運動行為調控的生理機制則仍待釐清。由於 MSN 細胞是藉由 -氨基丁酸 (GABA) 參與運動行為的控制，而負責GABA 生合成酵素之一的麩胺酸脫羧酵素-67 (GAD67) 的異常表現量被認為與巴金森氏症 (Parkinson’s disease) 引起之運動異常有相關性，但 GAD-67 的細胞調節機制仍待釐清，因此，論文研究的主軸是探討紋狀體 CK2 、 DARPP-32 和 GAD67 蛋白之間的訊息傳遞與神經傳遞物質和行為之間的關係。

研究結果發現在大鼠紋狀體轉染野生型 CK2α DNA 質體會增加 DARPP-32 Ser102的磷酸化程度及 GAD67 mRNA 的表現量；而轉染 CK2 siRNA 則會降低 DARPP-32 蛋白含量和 Ser102 的磷酸化程度、 GAD67 蛋白含量和 mRNA 的表現量和紋狀體的 GABA 含量。轉染 DARPP-32 siRNA會降低 GAD67 蛋白含量及 mRNA 表現量和紋狀體的 GABA 含量；轉染突變型 DARPP-32 S102A DNA 質體（模擬胺基酸不能被磷酸化） 同樣會減少紋狀體的 GABA 含量。此外，共同轉染 CK2α DNA 和 DARPP-32 S102A DNA 質體會抑制單獨轉染 CK2α DNA 對提升紋狀體GABA和多巴胺含量增加的作用。在紋狀體給予 CK2 siRNA 觀察到黑質腦區 (substantia nigra) 酪胺酸羥化酶 (tyrosine hydroxylase, TH) 蛋白表現減少，給予 DARPP-32 siRNA 則觀察到黑質 TH Ser40 胺基酸磷酸化減少。在 rota-rod 運動行為測試中也可發現，轉染 CK2 siRNA 會抑制多巴胺受體致效劑 SKF38393 對促進運動能力的效果。綜合論文實驗的結果推測在紋狀體 MSN 細胞中，蛋白激酶 CK2 對 DARPP-32 蛋白 Ser102 磷酸化作用的細胞機制除了參與 GAD67 蛋白和神經傳遞物質 GABA 以及大鼠運動行為的生理調控外，亦可能回饋影響黑質腦區多巴胺神經細胞的 TH 蛋白含量和磷酸化程度。
Protein kinase CK2 is a multifunctional serine/threonine protein kinase and involves in many neurophysiological functions including neuronal plasticity and neuroprotection, but its molecular mechanisms are not well investigated. Previous studies have shown that CK2 protein levels and activity are more elevated in the striatum than other brain areas. DARPP-32 (Dopamine- and cAMP-regulated phosphoprotein, Mr 32 kDa) is also highly enriched in striatal medium spiny GABAergic neurons and has been found the Ser102 residue is a phosphorylation site for CK2. Many studies have revealed that Ser34/Thr75 phosphorylation of DARPP-32 mediates dopamine signaling pathway which affects the physiological function and behavior in drug abuse. However, whether Ser102 phosphorylation by CK2 in the MSN controls motor behaviors is still unclear. Glutamic acid decarboxylase 67 (GAD67) which is one of the enzymes responsible for the synthesis of neurotransmitter GABA in the MSN and its dysfunction is presented relationship with Parkinson’s disease-induced behavior deficits. But the cellular regulatory mechanism of GAD67 is not fully studies. The aims of this proposal are to investigate the signaling relationship between CK2, DARPP-32 and GAD67 reflecting on neurotransmitter content in striatum and motor behavior in rats.
The present results demonstrates that DARPP-32 Ser102 phosphorylation status and GAD67 mRNA levels are increased by wild-type CK2 plasmid DNA transfection. CK2 siRNA treatment also decreased DARPP-32 protein levels and Ser102 phosphorylation status, GAD67 protein and mRNA levels as well as GABA levels in the striatum. On the other hand, DARPP-32 siRNA transfection decreased GAD67 protein and mRNA levels, as also GABA levels in the striatum. TH Ser40 phosphorylation level in the substantia nigra. Striatal GABA levelds were decreased by transfection of mutant DARPP-32 S102A, which mimics the un-phosphorylated by CK2. Co-express CK2 and DARPP-32 S102A plasmid DNA reduced GABA level which was induced by CK2alone. The striatal CK2 or DARPP-32 siRNA transfection decreased Tyrosine Hydroxylase (TH) protein level or TH Ser40 phosphorylation level in the substantia nigra. Furthermore, DA agonist SKF38393 induced motor behavior promotion was inhibited by CK2 siRNA transfection. All the current results suggest that cellular signaling of DARPP-32 Ser102 phosphorylation by CK2 not only mediates GAD67 protein expression and biosynthesis of GABA neurotransmitter in striatum and motor behavior of rats, but also might affect TH protein level and phosphorylation status in the substantia nigra.
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描述 碩士
國立政治大學
神經科學研究所
99754010
資料來源 http://thesis.lib.nccu.edu.tw/record/#G0099754010
資料類型 thesis
dc.contributor.advisor 趙知章zh_TW
dc.contributor.advisor Chao, Chi Changen_US
dc.contributor.author (作者) 黃鉉豐zh_TW
dc.contributor.author (作者) Huang, Xuan Fengen_US
dc.creator (作者) 黃鉉豐zh_TW
dc.creator (作者) Huang, Xuan Fengen_US
dc.date (日期) 2016en_US
dc.date.accessioned 1-三月-2016 10:41:29 (UTC+8)-
dc.date.available 1-三月-2016 10:41:29 (UTC+8)-
dc.date.issued (上傳時間) 1-三月-2016 10:41:29 (UTC+8)-
dc.identifier (其他 識別碼) G0099754010en_US
dc.identifier.uri (URI) http://nccur.lib.nccu.edu.tw/handle/140.119/81530-
dc.description (描述) 碩士zh_TW
dc.description (描述) 國立政治大學zh_TW
dc.description (描述) 神經科學研究所zh_TW
dc.description (描述) 99754010zh_TW
dc.description.abstract (摘要) 蛋白激酶 CK2 是一種針對受質蛋白之絲胺酸/蘇胺酸進行磷酸化之多種功能的蛋白激酶，參與調節包括神經可塑性和神經保護等許多神經系統的功能，但是其分子層面的細胞機制目前尚未完全釐清。研究發現CK2在紋狀體腦區的表現量與活性皆高於其他腦區，而紋狀體之中型多刺狀GABA 神經元（medium spiny neuron, MSN）中DARPP-32 (Dopamine- and cAMP-regulated phosphoprotein, Mr 32 kDa) 蛋白的Ser102胺基酸被證實是 CK2 的磷酸化作用位置。許多研究文獻證實在多巴胺訊息傳遞路徑中， DARPP-32 蛋白之 Ser34/Thr75 的磷酸化現象參與藥物成癮相關生理行為的作用，然而 Ser102 的磷酸化作用與 MSN 細胞對運動行為調控的生理機制則仍待釐清。由於 MSN 細胞是藉由 -氨基丁酸 (GABA) 參與運動行為的控制，而負責GABA 生合成酵素之一的麩胺酸脫羧酵素-67 (GAD67) 的異常表現量被認為與巴金森氏症 (Parkinson’s disease) 引起之運動異常有相關性，但 GAD-67 的細胞調節機制仍待釐清，因此，論文研究的主軸是探討紋狀體 CK2 、 DARPP-32 和 GAD67 蛋白之間的訊息傳遞與神經傳遞物質和行為之間的關係。

研究結果發現在大鼠紋狀體轉染野生型 CK2α DNA 質體會增加 DARPP-32 Ser102的磷酸化程度及 GAD67 mRNA 的表現量；而轉染 CK2 siRNA 則會降低 DARPP-32 蛋白含量和 Ser102 的磷酸化程度、 GAD67 蛋白含量和 mRNA 的表現量和紋狀體的 GABA 含量。轉染 DARPP-32 siRNA會降低 GAD67 蛋白含量及 mRNA 表現量和紋狀體的 GABA 含量；轉染突變型 DARPP-32 S102A DNA 質體（模擬胺基酸不能被磷酸化） 同樣會減少紋狀體的 GABA 含量。此外，共同轉染 CK2α DNA 和 DARPP-32 S102A DNA 質體會抑制單獨轉染 CK2α DNA 對提升紋狀體GABA和多巴胺含量增加的作用。在紋狀體給予 CK2 siRNA 觀察到黑質腦區 (substantia nigra) 酪胺酸羥化酶 (tyrosine hydroxylase, TH) 蛋白表現減少，給予 DARPP-32 siRNA 則觀察到黑質 TH Ser40 胺基酸磷酸化減少。在 rota-rod 運動行為測試中也可發現，轉染 CK2 siRNA 會抑制多巴胺受體致效劑 SKF38393 對促進運動能力的效果。綜合論文實驗的結果推測在紋狀體 MSN 細胞中，蛋白激酶 CK2 對 DARPP-32 蛋白 Ser102 磷酸化作用的細胞機制除了參與 GAD67 蛋白和神經傳遞物質 GABA 以及大鼠運動行為的生理調控外，亦可能回饋影響黑質腦區多巴胺神經細胞的 TH 蛋白含量和磷酸化程度。		zh_TW
dc.description.abstract (摘要) Protein kinase CK2 is a multifunctional serine/threonine protein kinase and involves in many neurophysiological functions including neuronal plasticity and neuroprotection, but its molecular mechanisms are not well investigated. Previous studies have shown that CK2 protein levels and activity are more elevated in the striatum than other brain areas. DARPP-32 (Dopamine- and cAMP-regulated phosphoprotein, Mr 32 kDa) is also highly enriched in striatal medium spiny GABAergic neurons and has been found the Ser102 residue is a phosphorylation site for CK2. Many studies have revealed that Ser34/Thr75 phosphorylation of DARPP-32 mediates dopamine signaling pathway which affects the physiological function and behavior in drug abuse. However, whether Ser102 phosphorylation by CK2 in the MSN controls motor behaviors is still unclear. Glutamic acid decarboxylase 67 (GAD67) which is one of the enzymes responsible for the synthesis of neurotransmitter GABA in the MSN and its dysfunction is presented relationship with Parkinson’s disease-induced behavior deficits. But the cellular regulatory mechanism of GAD67 is not fully studies. The aims of this proposal are to investigate the signaling relationship between CK2, DARPP-32 and GAD67 reflecting on neurotransmitter content in striatum and motor behavior in rats.
The present results demonstrates that DARPP-32 Ser102 phosphorylation status and GAD67 mRNA levels are increased by wild-type CK2 plasmid DNA transfection. CK2 siRNA treatment also decreased DARPP-32 protein levels and Ser102 phosphorylation status, GAD67 protein and mRNA levels as well as GABA levels in the striatum. On the other hand, DARPP-32 siRNA transfection decreased GAD67 protein and mRNA levels, as also GABA levels in the striatum. TH Ser40 phosphorylation level in the substantia nigra. Striatal GABA levelds were decreased by transfection of mutant DARPP-32 S102A, which mimics the un-phosphorylated by CK2. Co-express CK2 and DARPP-32 S102A plasmid DNA reduced GABA level which was induced by CK2alone. The striatal CK2 or DARPP-32 siRNA transfection decreased Tyrosine Hydroxylase (TH) protein level or TH Ser40 phosphorylation level in the substantia nigra. Furthermore, DA agonist SKF38393 induced motor behavior promotion was inhibited by CK2 siRNA transfection. All the current results suggest that cellular signaling of DARPP-32 Ser102 phosphorylation by CK2 not only mediates GAD67 protein expression and biosynthesis of GABA neurotransmitter in striatum and motor behavior of rats, but also might affect TH protein level and phosphorylation status in the substantia nigra.		en_US
dc.description.tableofcontents 第一章 緒論 1
第一節 多巴胺系統（Dopamine System） 2
第二節 DARPP-32蛋白（a dopamine- and cAMP-regulated phosphoprotein of Mr 32 kDa） 4
第三節 蛋白激酶 CK2（Protein kinase CK2, Casein kinase 2） 5
第四節 麩胺酸脫羧酶 67（Glutamic acid decarboxylase 67, GAD67） 7
第五節 論文研究目的與策略 8
第二章 實驗材料與方法 10
第一節 實驗動物 11
第二節 立體定位手術（stereotaxic surgery） 11
第三節 質體 DNA 配置和 DARPP-32 胺基酸 S102 磷酸化抗體製備 11
第四節 DNA 質體萃取 12
第五節 DNA質體與小干擾 RNA (siRNA) 的轉染作用 12
一、 質體 DNA 與聚乙烯亞胺 (polyethylenimine, PEI) 之製備與轉染反應 13
二、 小干擾 RNA 轉染作用 14
第六節 SKF38393 之配置及注射 14
第七節 藥物微量注射程序 15
一、 質體 DNA、小干擾 RNA 和 SKF38393 微量注射 15
二、 SKF38393 和 CK2siRNA 共同微量注射 15
第八節 西方墨點法（western blot） 15
一、 紋狀體及黑質體組織擷取 15
二、 蛋白質萃取 16
三、 蛋白質濃度測定及標準曲線製作 16
四、 蛋白質樣本配置 16
五、 鑄膠及聚丙烯醯胺凝膠電泳（sodium dodecyl sulfate polyacrylamide gel electrophoresis, SDS-PAGE） 17
六、 轉漬（transfer） 17
七、 免疫轉印（immunoblotting） 17
第九節 即時定量聚合酶連鎖反應 (Quantitative real-time polymerase chain reaction, Q-PCR) 18
一、 氧核醣核酸 (RNA) 之萃取 18
二、 轉 cDNA 19
三、 即時定量聚合酶連鎖反應 19
第十節 高效能液相層析法（High Performance Liquid Chromatography, HPLC） 19
一、 神經傳遞物質之萃取 20
二、 流動相（mobile phase）配置 20
三、 高效能液相層析法 20
第十一節 大鼠行為測試 20
一、 open field 20
二、 rota-rod 21
第十二節 統計分析 21
第三章 實驗結果 22
第一節 轉染野生型 CK2WT DNA 質體對大白鼠紋狀體腦區的蛋白質含量和磷酸化程度及表現量的影響 23
第二節 轉染 CK2 siRNA 對大白鼠紋狀體腦區蛋白質含量、磷酸化程度、mRNA 表現量和神經傳遞物質含量的影響 23
第三節 轉染 DARPP-32 siRNA 對大白鼠紋狀體腦區蛋白質含量、磷酸化程度、mRNA 表現量和神經傳遞物質含量的影響 24
第四節 轉染突變型 DARPP-32 102A 或 102D DNA 質體對大白鼠紋狀體腦區蛋白質含量、磷酸化程度和神經傳遞物質含量的影響 25
第五節 共同轉染野生型 CK2WT 與突變型 DARPP32 102A DNA 質體對大白鼠紋狀體腦區蛋白質含量、磷酸化程度和神經傳遞物質含量的影響 27
第六節 操控大白鼠紋狀體腦區 CK2、DARPP-32 基因表現對黑質腦區蛋白質含量及磷酸化程度的影響 28
第七節 SKF38393 與 CK2 siRNA 交互作用對大白鼠紋狀體和黑質腦區蛋白質含量、磷酸化程度和神經傳遞物質含量的影響 29
第八節 SKF38393 與 CK2 siRNA 交互作用對大白鼠運動行為 rota-rod treadmill 和 locomotor 的影響 31
第四章 討論 33
第五章 結論 41
實驗圖表 43
參考文獻 75
 		zh_TW
dc.source.uri (資料來源) http://thesis.lib.nccu.edu.tw/record/#G0099754010en_US
dc.subject (關鍵詞) 紋狀體zh_TW
dc.subject (關鍵詞) MSN 細胞zh_TW
dc.subject (關鍵詞) 蛋白激酶 CK2zh_TW
dc.subject (關鍵詞) DARPP-32 蛋白zh_TW
dc.subject (關鍵詞) 麩胺酸脫羧酵素-67zh_TW
dc.subject (關鍵詞) 酪胺酸羥化酶zh_TW
dc.subject (關鍵詞) 多巴胺zh_TW
dc.subject (關鍵詞) -丁氨基酪酸zh_TW
dc.subject (關鍵詞) striatumen_US
dc.subject (關鍵詞) medium spiny GABAergic neuronsen_US
dc.subject (關鍵詞) protein kinase CK2en_US
dc.subject (關鍵詞) DARPP-32en_US
dc.subject (關鍵詞) Glutamic acid decarboxylase 67en_US
dc.subject (關鍵詞) -aminobutyric aciden_US
dc.subject (關鍵詞) dopamineen_US
dc.subject (關鍵詞) Tyrosine Hydroxylaseen_US
dc.title (題名) 大鼠紋狀體腦區 CK2/DARPP-32/GAD67 蛋白細胞訊息傳遞路徑對神經傳遞物質和運動行為影響之探討zh_TW
dc.title (題名) The influence of striatal CK2/DARPP-32/GAD67 signaling pathway on neurotransmitter and motor behavior of ratsen_US
dc.type (資料類型) thesisen_US
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