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完整後設資料紀錄
DC 欄位 | 值 | 語言 |
---|---|---|
dc.contributor.advisor | 陳瑞華 | |
dc.contributor.author | Pei-Rung Wu | en |
dc.contributor.author | 吳佩容 | zh_TW |
dc.date.accessioned | 2021-06-08T05:03:42Z | - |
dc.date.copyright | 2011-10-05 | |
dc.date.issued | 2011 | |
dc.date.submitted | 2011-02-24 | |
dc.identifier.citation | References
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dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/23539 | - |
dc.description.abstract | 死亡相關蛋白激酶(Death-associated protein kinase, DAPK)是一個促進死亡,由鈣/攜鈣素所調節的絲氨酸/蘇氨酸激酶。DAPK在腦內大量存在,並調節好幾種神經死亡或傷害的情況。此外,遺傳實驗發現兩個在DAPK基因座上的單核甘酸多型性(single nucleotide polymorphisms, SNPs)和遲發性阿滋海默症有高度關聯,而這兩個SNPs和對偶基因特異性表現相關,暗示DAPK的基因差異調控遲發性阿滋海默症的敏感性。已知DAPK促進細胞死亡的能力有一部分是透過肌動蛋白細胞骨架(actin cytoskeletons),在此,我們發現DAPK會活化微管親合性調控激酶(MAP/microtubule affinity regulating kinase, MARK) 1/2,進而抑制微管組合(microtubule assembly)。已知MARK1/2會磷酸化微管相關蛋白(microtubule-associated protein, MAP),包括MAP2/4和tau。MARK2的活性增加,也促使tau絲氨酸262殘基的磷酸化增加,進而影響 tau和微管的接合,而使tau無法繼續穩定微管,因此,DAPK促進由MARK1/2所造成的微管破壞現象。特別的是,對於活化MARK1/2,DAPK的死亡區塊(death domain)是必須且足夠的,而不需要DAPK的酵素能力。死亡區塊和MARK1/2的間隔區域(spacer region)結合,引起MARK1/2構型改變,而將它從自我抑制中釋放。因此,我們發現在DAPK基因剔除小鼠的腦組織中,絲氨酸262殘基的磷酸化會降低;也發現DAPK會促進MARK1/2功能而調控極化軸索向外生長(polarized neurite outgrowth)。利用果蠅系統,我們發現大量表現包含死亡區塊的DAPK可引起毛糙眼(rough eye)和光受器神經元(photoreceptor neuron)的流失,而這樣的現象是透過PAR-1 (MARK在果蠅的同源基因) 和tau所造成的,並和tau的絲氨酸262殘基磷酸化有關。總結,由上述的實驗,我們發現DAPK可以增進MARK1/2的激酶活性,進而調控它的生物功能,包含微管組合、神經分化、及和阿滋海默症相關的tau毒性。 | zh_TW |
dc.description.abstract | Death-associated protein kinase (DAPK) is a key player in several modes of neuronal death/injury and has been implicated in the late-onset Alzheimer’s disease (AD). DAPK promotes cell death partly through its effect on regulating actin cytoskeletons. Here, we report that DAPK inhibits microtubule (MT) assembly by activating MARK/PAR-1 family kinases MARK1/2, which destabilize MT by phosphorylating tau and related MAP2/4. DAPK death domain, but not catalytic activity, is responsible for this activation by binding to MARK1/2 spacer region, thereby disrupting an intramolecular interaction that inhibits MARK1/2. Accordingly, DAPK-/- mice brain displays a reduction of tau phosphorylation and DAPK enhances the effect of MARK2 on regulating polarized neurite outgrowth. Using a well characterized Drosophila model of tauopathy, we show that DAPK acts in part through MARK Drosophila ortholog PAR-1 to induce rough eye and loss of photoreceptor neurons. Furthermore, DAPK enhances tau toxicity through a PAR-1 phosphorylation-dependent mechanism. Together, our study reveals a novel mechanism of MARK activation, uncovers DAPK functions in modulating MT assembly and neuronal differentiation, and provides a molecular link of DAPK to tau phosphorylation, an event associated with AD pathology. | en |
dc.description.provenance | Made available in DSpace on 2021-06-08T05:03:42Z (GMT). No. of bitstreams: 1 ntu-100-F93448001-1.pdf: 10822274 bytes, checksum: cd6f627da8704ff86c2f90697e11a64a (MD5) Previous issue date: 2011 | en |
dc.description.tableofcontents | Table of Content
口試委員會審定書 誌謝………….…………………………………………………………….……….…1 中文摘要………………………………………….………………………….…….…2 Abstract………………………………………………………………………………3 Table of Content…………………………………………………………….….……4 Abbreviations……………………………………………………………….………..8 Chpater I Literature review…………………………….……………………….…11 1. Alzheimer’s disease (AD) ……………………….…………………..………...…11 1.1 The pathologic features of AD…………………………………………….……11 1.2 The putative molecular mechanisms of AD…………….……………...…….…11 1.2.1 Amyloid-β (Aβ) peptide…………………………………….…………….…11 1.2.2 Tau toxicity…………………………………………...……………...…...…13 1.2.3 Apolipoprotein E (APOE) ……………………...…………………….….….13 1.3 Animal models to investigate AD...…………………….……….……….…..…14 1.3.1 Mus musculus (M. musculus).....…………………….…………….......….…14 1.3.2 Drosophila melanogaster (D. melanogaster) ...…………………….....….…14 1.3.3 Caenorhabditis elegans (C. elegans)....………...………….….……...…..…15 1.3.4 Petromyzon marinus (P. marinus) ...………...................….…………..….…15 1.4 Therapeutic strategies of AD...……………………………….…………..…..…15 1.4.1 The medications approved by FDA for AD treatment………………..…..…15 1.4.2 Other medications and alternative treatments for AD……….…….….…..…16 1.4.3 The potential drugs in the clinical trials and preclinical studies as well as other therapeutic strategies……………………………………………….…….….…….16 2. Microtubule (MT) ………………………………..........................………..….…18 2.1 The composition of MT………………………………...…….…………..….…18 2.2 The role of MT in a cell…………………………………...…….………..….…20 2.3 MT is regulated by several factors………………………………...….…..….…21 2.3.1 MT polymerases and depolymerases…………………………….…....….…21 2.3.2 Microtubule-severing enzymes………………………….…….……...…..…22 2.3.3 Microtubule-associated proteins (MAPs) ..…………….…..……….....….…22 2.3.4 MT plus-end tracking proteins (+TIPs) ..…………………..……..…...….…23 2.3.5 Post-translational modifications on MT…………………………........…..…25 2.3.6 Tubulin-binding agents (TBAs) …………………………………..…..….…28 3. Death associated protein kinase (DAPK) .…………………..….…….......….…29 3.1 The structure and family members of DAPK……………………..……....….…29 3.2 The expression pattern of DAPK………………………………..…….….….…30 3.3 The regulations of DAPK ………………………………………….……..….…31 3.4 The functions of DAPK…………………………………………………...….…32 3.4.1 DAPK is a tumor suppressor………………………….……………….….…32 3.4.2 DAPK causes autophagy…………………….………………….………...…33 3.4.3 DAPK plays a role in immunity…………………….…………….…………33 3.4.4 The function of DAPK in neuronal system…………………….….……...…34 4. MAP/microtubule affinity regulating kinase 2 (MARK2) ………………….…35 4.1 The structure of MARK2 and its family members………………………..….…35 4.2 The expression pattern of MARK2……….……………………………….....…36 4.3 The functions of MARK2…………………….………………………..….….…37 4.3.1 MARK2 functions on cytoskeleton………. ……………….……….…….…37 4.3.2 MARK2 functions in neuronal system…………………….……….….….…37 4.3.3 MARK is a key player of polarity………………….……………….…….…38 4.3.4 Other functions of MARK2.……………………….……………….……..…39 4.4 How is MARK2 regulated? ……………………. ……………….…………..…40 4.4.1 Phosphorylation of MARK2 affects its activity and cellular localization.…..40 4.4.2 Protein-protein interaction influences MARK2 function……………..…..…41 Chapter II DAPK activates MARK1/2 to regulate microtubule assembly, neuronal differentiation, and tau toxicity…………………………….……..….…42 Introduction…………………………….………………….…………….…....….…42 Materials and methods…………………………………..……….…………...….…43 Cell culture and transfection……………………………….……….………....……43 Plasmids……….…. …………………………….………………..……….……..…44 RNA interference……….……………………………….………………..….…..…44 Antibodies……….….…………………………….………………………….…..…45 Generation of baculovirus………………………………….…………….…...….…45 Detergent extraction for separating soluble and insoluble proteins...………..…..…45 Immunoprecipitation.……….….……………………………….…………….….…45 GST pull down……….….…………………………………...……….……...……..46 Kinase assay……….….……………………………….………………...….………46 Immunofluorescence analysis………………………………….….….....…....….…46 Live-cell image and data analysis……….……………………….……..…….….…47 Fly stocks and genetics……….…. …………………………….………..….…....…47 Histology and immunohistochemistry……….…………………….………..…...…48 Analysis of protein expression in mice and Drosophila ……………..…..…..….…48 Acknowledgments………..…………………………….………………….…….…48 Results………………………………….………………..…...…………..…...….….49 DAPK inhibits MT assembly..……….….………………………..…………..….…49 DAPK activates MARK1 and MARK2…………………………….…..….….……49 DAPK activates MARK2 to promote tau phosphorylation in neurons.………….…50 DAPK relieves MARK1/2 autoinhibition by interacting with their spacer regions..51 DAPK-MARK signaling axis inhibits MT assembly and stability...………..…..….52 DAPK enhances the effect of MARK2 on axon formation………..……….…...…..52 DAPK induces rough eye and photoreceptor loss through PAR-1.……..….…...…..52 DAPK enhances tau toxicity through a tau S262-dependent mechanism.……….…53 Discussion…………………………………………………………………….….…..55 References………………………………….……………………………..….….…..57 Figures……………………………………………………………..……………...…82 Figure 1 Steady-state MT morphology in DAPK- or mock-transfected cells.…..….82 Figure 2 DAPK inhibits MT assembly.………………………………………...…...82 Figure 3 DAPK reduces MT regrowth in several types of cells.………………...…83 Figure 4 Measurement of MT growth velocities in HCC36 cells expressing DAPK or control vector..…………………………………………………………….……...…84 Figure 5 DAPK reduces MT growth velocity in differentiated N2a cells.……...…..84 Figure 6 DAPK does not affect MT nucleation at the centrosome…………………85 Figure 7 Flag-DAPK interacts with endogenous MARK1 and MARK2.….........….86 Figure 8 Flag-MARK1 and Flag-MARK2 interact with endogenous DAPK........…86 Figure 9 DAPK activates MARK1 and MARK2...................................................…87 Figure 10 DAPK does not phosphorylate tau….....................................................…88 Figure 11 DAPK catalytic activity is not affected by MARK1 or MARK2..........…88 Figure 12 DAPK promotes MARK2-induced tau phosphorylation at S262 in vivo…………………………………………………………………………..……...89 Figure 13 DAPK siRNA downregulates MARK2-induced tau S262 phosphorylation..……………………………………………………………..…......89 Figure 14 DAPK interacts with MARK2 endogenously..………………….….........90 Figure 15 Detection of DAPK and MARK2 interaction in both soluble and insoluble compartments of cells………………………………….………………...….….…...90 Figure 16 The specificities of DAPK and MARK2 antibodies…………………......91 Figure 17 Localization of DAPK and MARK2 in hippocampal neuron.……….......92 Figure 18 Endogenous DAPK promotes MARK2-induced tau S262 phosphorylation in neurons…………………………………………………………..………...……..92 Figure 19 DAPK knockdown impairs MARK2-induced tau S262 phosphorylation and MARK1/2 knockdown blocks DAPK-induced tau S262 phosphorylation in primary neurons…………………………………………………………..………...93 Figure 20 Reduced tau S262 phosphorylation in DAPK-/- mice…………..…...…...93 Figure 21 DAPK DD is responsible for MARK2 activation……………..…..….....94 Figure 22 The spacer region is required for MARK2 activation by DAPK…….......95 Figure 23 DAPK DD interacts with MARK2 spacer region……………..………....95 Figure 24 DAPK DD disrupts MARK2 intramolecular interaction….…..……........96 Figure 25 DAPK relieves MARK2 autoinhibition………………………..…….......96 Figure 26 DAPK DD interacts with the spacer region of MARK1………..…...…...97 Figure 27 Disrupting or mimicking MARK2 T595 phosphorylation does not affect its interaction with DAPK………………………..……... ……………………...….97 Figure 28 DAPK does not affect MARK1/2 phosphorylation at their activation loops……………….…………………..…….........……………………….……......98 Figure 29 Phosphorylation of MARK2 activation loop does not affect its binding to DAPK……………….…………………..…….........……………………….……....98 Figure 30 DAPK coordinates with MARK2 to disrupt MT stability……….……....99 Figure 31 DAPK enhances MARK2 ability to modulate MT regrowth……….….100 Figure 32 DAPK coordinates with MARK1/2 to modulate MT assembly……..…100 Figure 33 DAPK enhances the inhibitory effect of MARK2 on axon formation....101 Figure 34 DAPK knockdown reverses the inhibitory effect of MARK2 on axon formation………….…………………..…….........……………………….……….101 Figure 35 DAPK and DAPK K42A promote eye degeneration partly through DD..……..…………..….…………………..…….........………………………..…102 Figure 36 DAPK DD binds to the spacer region of PAR-1..………………….…...102 Figure 37 DAPK and DAPK K42A cause eye degeneration partially through Drosophila PAR-1….…………………..…….........……………………….……...103 Figure 38 Quantitative analysis of photoreceptor neurons in indicated transgenic flies….…………………..…….........……………………….………………….….103 Figure 39 DAPK enhances the eye degeneration phenotype of PAR-1……….…..104 Figure 40 DAPK and DAPK K42A lead to eye degeneration in part through Drosophila tau..……..…….........……………..………….…………………..…....105 Figure 41 DAPK expression levels in indicated transgenic flies were analyzed by immunoblot……………………………………….…………….………...…….…105 Figure 42 DAPK enhances the rough eye phenotype of tau……………..…....…..106 Appendix………………………………………….…………….……………….…107 | |
dc.language.iso | en | |
dc.title | DAPK活化MARK1/2進而調控微管組合、神經分化和tau毒性 | zh_TW |
dc.title | DAPK activates MARK1/2 to regulate microtubule assembly, neuronal differentiation, and tau toxicity | en |
dc.type | Thesis | |
dc.date.schoolyear | 99-2 | |
dc.description.degree | 博士 | |
dc.contributor.oralexamcommittee | 呂勝春,簡正鼎,陳光超,杜邦憲,黃怡萱 | |
dc.subject.keyword | 死亡相關蛋白激酶,微管親合性調控激酶,tau 磷酸化,神經退化,微管, | zh_TW |
dc.subject.keyword | DAPK,MARK/PAR-1,tau phosphorylation,neurodegeneration,microtubules, | en |
dc.relation.page | 106 | |
dc.rights.note | 未授權 | |
dc.date.accepted | 2011-02-24 | |
dc.contributor.author-college | 醫學院 | zh_TW |
dc.contributor.author-dept | 分子醫學研究所 | zh_TW |
顯示於系所單位: | 分子醫學研究所 |
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