跳到主要內容

臺灣博碩士論文加值系統

(3.236.50.201) 您好!臺灣時間:2021/08/06 07:33
字體大小: 字級放大   字級縮小   預設字形  
回查詢結果 :::

詳目顯示

我願授權國圖
: 
twitterline
研究生:程靜暐
研究生(外文):Ching-Wei Cheng
論文名稱:以果蠅模式探討TDP-43蛋白在神經退化性疾病所扮演的角色與治療對策
論文名稱(外文):A Drosophila Model to Investigate the Role of TDP-43 in Neurodegenerative Diseases and Its Therapeutic Application
指導教授:沈哲鯤沈哲鯤引用關係
指導教授(外文):Che-Kun James Shen
口試委員:簡正鼎孫以瀚李秀香潘俊良
口試委員(外文):Cheng-Ting ChienY. Henry SunHsiu-Hsiang LeeChun-Liang Pan
口試日期:2015-07-27
學位類別:博士
校院名稱:國立臺灣大學
系所名稱:分子醫學研究所
學門:醫藥衛生學門
學類:醫學學類
論文種類:學術論文
論文出版年:2015
畢業學年度:103
語文別:英文
論文頁數:157
中文關鍵詞:肌萎縮性脊髓側索硬化症額顳葉型失智症TDP-43蛋白果蠅模型果蠅蘑菇體運動能力生存曲線
外文關鍵詞:TDP-43amyotrophic lateral sclerosisfrontotemporal lobar degenerationDrosophilalifespanlocomotor activitymushroom body
相關次數:
  • 被引用被引用:0
  • 點閱點閱:135
  • 評分評分:
  • 下載下載:0
  • 收藏至我的研究室書目清單書目收藏:0
TDP-43是一種多功能的RNA / DNA結合蛋白,存在於多種物種中,如哺乳動物和果蠅;在某些類型的肌萎縮性脊髓側索硬化症(ALS-TDP)與額顳葉型失智症病人(FTLD-TDP)中,TDP-43會以異常的形式出現在堆積蛋白內,目前為止,並無有效的藥物可以治療這些神經退化疾病。在此論文中,我利用果蠅TDP-43的同源蛋白-dTDP,建立一套果蠅模型來探討TDP-43的功能,同時作為藥物測試的平台。藉由調控dTDP的表現,發現果蠅個體若喪失dTDP的表現,會嚴重影響其發育以及其運動能力;而在蘑菇體、運動神經元或是PDF(+)神經元中過量表現dTDP,則會出現神經退化的病變,而這些病變和dTDP的含量或是個體年齡成正相關;此外在蘑菇體過量表現dTDP,還會影響學習能力。由此可見dTDP對於個體的發育與神經功能的維持是很重要的。接著,利用‘TARGET’系統建立ALS-TDP果蠅模型,以溫度調控dTDP在運動神經元的表現,進而避免dTDP對發育早期的不良影響。如同ALS病人般,ALS-TDP果蠅的壽命會縮短且運動能力會下降;進一步觀察胸腔神經節的T1/T2區域,發現神經元較正常果蠅少,同時會有dTDP的堆積蛋白形成。因此利用這個ALS-TDP果蠅模型作為藥物測試的平台;我選用一個會活化自噬作用的藥物-雷帕黴素來測試。結果發現高劑量的雷帕黴素會些微改善ALS-TDP果蠅的運動缺陷和存活天數,以及減少含有dTDP堆積蛋白的神經元數目。另外利用此ALS-TDP果蠅模型,還發現S6K是dTDP的genetic modifier。綜合以上結果,意味著TDP-43在神經發育過程中扮演重要角色,若TDP-43失去調控,將導致神經退化疾病。而本論文所建立的ALS-TDP模型,適合用來快速篩選治療ALS新藥的平台;同時亦佐證近幾年的研究,即自噬作用的活化劑,包括雷帕黴素和其衍生物,在治療ALS與TDP-43 proteinopathies是有開發潛力的藥物。

TDP-43 is a multi-functional RNA/DNA-binding protein well-conserved among many species including mammals and Drosophila. However, it is also a major component of the pathological inclusions associated with degenerating motor neurons of amyotrophic lateral sclerosis (ALS-TDP). Further, TDP-43 is a signature protein in one subtype of frontotemporal degeneration, FTLD-TDP. Unfortunately, there are no effective drugs for these neurodegenerative diseases. In this thesis, fly models are generated to explore the function and dysfunction of TDP-43. By both down- and up-regulation of the levels of Drosophila ortholog of TDP-43, dTDP, ubiquitously or in specific cell types/ tissues, the important role of the dTDP protein and by implication the mammalian TDP-43 protein as well, in development and in neuronal functioning are examined. For the latter in particular, I show that dTDP regulates learning ability and locomotion of the fruit flies. As a model of the TDP-43 proteinopathies, flies with overexpression of dTDP, either in the mushroom body, in motor neurons, or in PDF (+) neurons, also exhibit dose-dependent and/or age-dependent pathogenesis behavior.
Next, I establish a fly model of ALS-TDP with transgenic expression of dTDP in adult flies under the control of a temperature sensitive motor neuron-specific GAL4, thus bypassing the deleterious effect of dTDP during development. These ALS-TDP flies also exhibit diminished lifespan as well as locomotor defects following induction of dTDP. Dissection of the T1/T2 region of the thoracic ganglia has revealed loss of the neurons and the formation of dTDP (+) aggregates. Since the ALS-TDP flies exhibit diseased phenotypes, I utilize this model to examine the therapeutic effect of rapamycin, a TOR-dependent autophagy activator. Although harmful to the control flies, administration of 400

口試委員會審定書Thesis Approval Form.......................i
誌謝 Acknowledgment.......................................ii
中文摘要Chinese Abstract.................................iii
英文摘要English Abstract..................................iv
關鍵字縮寫Abbreviation....................................vi
目錄Table of Contents...................................viii
圖目錄List of Figures.....................................xi
表目錄List of Tables.....................................xii
INTRODUCTION...............................................1
I.TDP-43: the protein structure and its cellular functions.1
II.The similarity between TDP-43 and Drosophila dTDP.......2
III.FTLD, ALS and TDP-43 proteinopathies...................3
IV.TDP-43 and the pathogenesis of FTLD-TDP and ALS-TDP.....5
V.Autophagy................................................7
VI.Targeting to autophagy in neurodegenerative diseases....8
MATERIALS AND METHODS.....................................10
I.Fly stocks and husbandry................................10
II.RNA isolation and RT-PCR...............................11
III.dTDP antibody generation..............................11
IV.Rapamycin treatment....................................12
V.Locomotor activity assay…………………………………………12
VI.Odor avoidance learning test...........................13
VII.Longevity.............................................13
VIII.Western blotting.....................................14
IX.Immunostaining assay...................................15
X.Statistical analysis....................................17
RESULTS...................................................18
I.Regulation of development and motility by dTDP……………18
II.The cognitive behavior and the morphology of mushroom body of Drosophila with knockdown or overexpression of dTDP in the mushroom bodies....................................19
III.Larval and adult phenotypes of flies with overexpression of dTDP in the motor neurons...............23
IV.Larval and adult phenotypes of flies with overexpression of dTDP in the PDF (+) neurons............................27
V.Overexpression of dTDP in the motor neurons under temporal UAS/GAL4 control also causes neuronal loss in the thoracic ganglia and exhibits the phenotypes of shortened lifespan and decreased locomotor activity.................29
VI.Rapamycin partially prevented the development of pathology of the fly model of ALS-TDP through activation of autophagy.................................................31
VII.Increased S6K activity reduces lifespan of the ALS-TDP flies.....................................................33
DISCUSSIONS...............................................35
I.Loss of dTDP causes developmental and locomotive defects...................................................35
II.Overexpression of dTDP causes ALS-TDP or FTLD-TDP phenotypes................................................36
III.Establishment of a drug screening model of ALS-TDP....39
REFERENCES................................................46
APPENDICES...............................................100

圖目錄 List of Figures
Figure 1. ................................................65
Figure 2. ................................................67
Figure 3. ................................................68
Figure 4. ................................................69
Figure 5. ................................................71
Figure 6. ................................................73
Figure 7. ................................................75
Figure 8. ................................................76
Figure 9. ................................................78
Figure 10. ...............................................79
Figure 11. ...............................................80
Figure 12. ...............................................82
Figure 13. ...............................................83
Figure 14. ...............................................84
Figure 15. ...............................................85
Figure 16. ...............................................86
Figure 17. ...............................................87
Figure 18. ...............................................88
Figure 19. ...............................................90
Figure 20. ...............................................91
Figure 21. ...............................................92
Figure 22. ...............................................93
Figure 23. ...............................................95
Figure 24. ...............................................96

表目錄 List of Tables
Table 1. .................................................97
Table 2. .................................................98
Table 3. .................................................99

Aoki, N., Murray, M.E., Ogaki, K., Fujioka, S., Rutherford, N.J., Rademakers, R., Ross, O.A., and Dickson, D.W. (2015). Hippocampal sclerosis in Lewy body disease is a TDP-43 proteinopathy similar to FTLD-TDP Type A. Acta Neuropathol, 129, 53-64.
Arai, T., Hasegawa, M., Nonoka, T., Kametani, F., Yamashita, M., Hosokawa, M., Niizato, K., Tsuchiya, K., Kobayashi, Z., Ikeda, K., et al. (2010). Phosphorylated and cleaved TDP-43 in ALS, FTLD and other neurodegenerative disorders and in cellular models of TDP-43 proteinopathy. Neuropathology, 30, 170-181.
Armstrong, G.A., and Drapeau, P. (2013). Calcium channel agonists protect against neuromuscular dysfunction in a genetic model of TDP-43 mutation in ALS. J Neurosci, 33, 1741-1752.
Ayala, Y.M., Misteli, T., and Baralle, F.E. (2008). TDP-43 regulates retinoblastoma protein phosphorylation through the repression of cyclin-dependent kinase 6 expression. Proc Natl Acad Sci U S A, 105, 3785-3789.
Ayala, Y.M., Pantano, S., D''Ambrogio, A., Buratti, E., Brindisi, A., Marchetti, C., Romano, M., and Baralle, F.E. (2005). Human, Drosophila, and C.elegans TDP43: nucleic acid binding properties and splicing regulatory function. J Mol Biol, 348, 575-588.
Barmada, S.J., Serio, A., Arjun, A., Bilican, B., Daub, A., Ando, D.M., Tsvetkov, A., Pleiss, M., Li, X., Peisach, D., et al. (2014). Autophagy induction enhances TDP43 turnover and survival in neuronal ALS models. Nat Chem Biol, 10, 677-685.
Benzer, S. (1967). BEHAVIORAL MUTANTS OF Drosophila ISOLATED BY COUNTERCURRENT DISTRIBUTION. Proc Natl Acad Sci U S A, 58, 1112-1119.
Bose, J.K., Huang, C.C., and Shen, C.K. (2011). Regulation of autophagy by neuropathological protein TDP-43. J Biol Chem, 286, 44441-44448.
Bose, J.K., Wang, I.F., Hung, L., Tarn, W.Y., and Shen, C.K. (2008). TDP-43 overexpression enhances exon 7 inclusion during the survival of motor neuron pre-mRNA splicing. J Biol Chem, 283, 28852-28859.
Brady, O.A., Meng, P., Zheng, Y., Mao, Y., and Hu, F. (2011). Regulation of TDP-43 aggregation by phosphorylation and p62/SQSTM1. J Neurochem, 116, 248-259.
Buratti, E., and Baralle, F.E. (2001). Characterization and functional implications of the RNA binding properties of nuclear factor TDP-43, a novel splicing regulator of CFTR exon 9. J Biol Chem, 276, 36337-36343.
Buratti, E., and Baralle, F.E. (2009). The molecular links between TDP-43 dysfunction and neurodegeneration. Adv Genet, 66, 1-34.
Buratti, E., Brindisi, A., Giombi, M., Tisminetzky, S., Ayala, Y.M., and Baralle, F.E. (2005). TDP-43 binds heterogeneous nuclear ribonucleoprotein A/B through its C-terminal tail: an important region for the inhibition of cystic fibrosis transmembrane conductance regulator exon 9 splicing. J Biol Chem, 280, 37572-37584.
Buratti, E., De Conti, L., Stuani, C., Romano, M., Baralle, M., and Baralle, F. (2010). Nuclear factor TDP-43 can affect selected microRNA levels. FEBS J, 277, 2268-2281.
Buratti, E., Dork, T., Zuccato, E., Pagani, F., Romano, M., and Baralle, F.E. (2001). Nuclear factor TDP-43 and SR proteins promote in vitro and in vivo CFTR exon 9 skipping. EMBO J, 20, 1774-1784.
Caccamo, A., Majumder, S., Deng, J.J., Bai, Y., Thornton, F.B., and Oddo, S. (2009). Rapamycin rescues TDP-43 mislocalization and the associated low molecular mass neurofilament instability. J Biol Chem, 284, 27416-27424.
Caccamo, A., Majumder, S., Richardson, A., Strong, R., and Oddo, S. (2010). Molecular interplay between mammalian target of rapamycin (mTOR), amyloid-beta, and Tau: effects on cognitive impairments. J Biol Chem, 285, 13107-13120.
Chen-Plotkin, A.S., Lee, V.M., and Trojanowski, J.Q. (2010). TAR DNA-binding protein 43 in neurodegenerative disease. Nat Rev Neurol, 6, 211-220.
Chiang, P.M., Ling, J., Jeong, Y.H., Price, D.L., Aja, S.M., and Wong, P.C. (2010). Deletion of TDP-43 down-regulates Tbc1d1, a gene linked to obesity, and alters body fat metabolism. Proc Natl Acad Sci U S A, 107, 16320-16324.
Colombrita, C., Zennaro, E., Fallini, C., Weber, M., Sommacal, A., Buratti, E., Silani, V., and Ratti, A. (2009). TDP-43 is recruited to stress granules in conditions of oxidative insult. J Neurochem, 111, 1051-1061.
Connolly, J.B., Roberts, I.J., Armstrong, J.D., Kaiser, K., Forte, M., Tully, T., and O''Kane, C.J. (1996). Associative learning disrupted by impaired Gs signaling in Drosophila mushroom bodies. Science, 274, 2104-2107.
Crews, L., Spencer, B., Desplats, P., Patrick, C., Paulino, A., Rockenstein, E., Hansen, L., Adame, A., Galasko, D., and Masliah, E. (2010). Selective molecular alterations in the autophagy pathway in patients with Lewy body disease and in models of alpha-synucleinopathy. PLoS One, 5, e9313.
D''Ambrogio, A., Buratti, E., Stuani, C., Guarnaccia, C., Romano, M., Ayala, Y.M., and Baralle, F.E. (2009). Functional mapping of the interaction between TDP-43 and hnRNP A2 in vivo. Nucleic Acids Res, 37, 4116-4126.
Dewey, C.M., Cenik, B., Sephton, C.F., Dries, D.R., Mayer, P., 3rd, Good, S.K., Johnson, B.A., Herz, J., and Yu, G. (2011). TDP-43 is directed to stress granules by sorbitol, a novel physiological osmotic and oxidative stressor. Mol Cell Biol, 31, 1098-1108.
Diaper, D.C., Adachi, Y., Sutcliffe, B., Humphrey, D.M., Elliott, C.J., Stepto, A., Ludlow, Z.N., Vanden Broeck, L., Callaerts, P., Dermaut, B., et al. (2013). Loss and gain of Drosophila TDP-43 impair synaptic efficacy and motor control leading to age-related neurodegeneration by loss-of-function phenotypes. Hum Mol Genet, 22, 1539-1557.
Dreumont, N., Hardy, S., Behm-Ansmant, I., Kister, L., Branlant, C., Stevenin, J., and Bourgeois, C.F. (2010). Antagonistic factors control the unproductive splicing of SC35 terminal intron. Nucleic Acids Res, 38, 1353-1366.
Estes, P.S., Boehringer, A., Zwick, R., Tang, J.E., Grigsby, B., and Zarnescu, D.C. (2011). Wild-type and A315T mutant TDP-43 exert differential neurotoxicity in a Drosophila model of ALS. Hum Mol Genet, 20, 2308-2321.
Feiguin, F., Godena, V.K., Romano, G., D''Ambrogio, A., Klima, R., and Baralle, F.E. (2009). Depletion of TDP-43 affects Drosophila motoneurons terminal synapsis and locomotive behavior. FEBS Lett, 583, 1586-1592.
Fiesel, F.C., Voigt, A., Weber, S.S., Van den Haute, C., Waldenmaier, A., Gorner, K., Walter, M., Anderson, M.L., Kern, J.V., Rasse, T.M., et al. (2010). Knockdown of transactive response DNA-binding protein (TDP-43) downregulates histone deacetylase 6. EMBO J, 29, 209-221.
Freibaum, B.D., Chitta, R.K., High, A.A., and Taylor, J.P. (2010). Global analysis of TDP-43 interacting proteins reveals strong association with RNA splicing and translation machinery. J Proteome Res, 9, 1104-1120.
Gendron, T.F., Josephs, K.A., and Petrucelli, L. (2010). Review: transactive response DNA-binding protein 43 (TDP-43): mechanisms of neurodegeneration. Neuropathol Appl Neurobiol, 36, 97-112.
Geser, F., Lee, V.M., and Trojanowski, J.Q. (2010). Amyotrophic lateral sclerosis and frontotemporal lobar degeneration: a spectrum of TDP-43 proteinopathies. Neuropathology, 30, 103-112.
Ghavami, S., Shojaei, S., Yeganeh, B., Ande, S.R., Jangamreddy, J.R., Mehrpour, M., Christoffersson, J., Chaabane, W., Moghadam, A.R., Kashani, H.H., et al. (2014). Autophagy and apoptosis dysfunction in neurodegenerative disorders. Prog Neurobiol, 112, 24-49.
Gijselinck, I., Sleegers, K., Engelborghs, S., Robberecht, W., Martin, J.J., Vandenberghe, R., Sciot, R., Dermaut, B., Goossens, D., van der Zee, J., et al. (2009). Neuronal inclusion protein TDP-43 has no primary genetic role in FTD and ALS. Neurobiol Aging, 30, 1329-1331.
Glick, D., Barth, S., and Macleod, K.F. (2010). Autophagy: cellular and molecular mechanisms. J Pathol, 221, 3-12.
Godena, V.K., Romano, G., Romano, M., Appocher, C., Klima, R., Buratti, E., Baralle, F.E., and Feiguin, F. (2011). TDP-43 regulates Drosophila neuromuscular junctions growth by modulating Futsch/MAP1B levels and synaptic microtubules organization. PLoS One, 6, e17808.
Gregory, J.M., Barros, T.P., Meehan, S., Dobson, C.M., and Luheshi, L.M. (2012). The aggregation and neurotoxicity of TDP-43 and its ALS-associated 25 kDa fragment are differentially affected by molecular chaperones in Drosophila. PLoS One, 7, e31899.
Grolleau, A., Bowman, J., Pradet-Balade, B., Puravs, E., Hanash, S., Garcia-Sanz, J.A., and Beretta, L. (2002). Global and specific translational control by rapamycin in T cells uncovered by microarrays and proteomics. J Biol Chem, 277, 22175-22184.
Guerreiro, R.J., Schymick, J.C., Crews, C., Singleton, A., Hardy, J., and Traynor, B.J. (2008). TDP-43 is not a common cause of sporadic amyotrophic lateral sclerosis. PLoS One, 3, e2450.
Hanson, K.A., Kim, S.H., Wassarman, D.A., and Tibbetts, R.S. (2010). Ubiquilin modifies TDP-43 toxicity in a Drosophila model of amyotrophic lateral sclerosis (ALS). J Biol Chem, 285, 11068-11072.
Harris, H., and Rubinsztein, D.C. (2012). Control of autophagy as a therapy for neurodegenerative disease. Nat Rev Neurol, 8, 108-117.
Hazelett, D.J., Chang, J.C., Lakeland, D.L., and Morton, D.B. (2012). Comparison of parallel high-throughput RNA sequencing between knockout of TDP-43 and its overexpression reveals primarily nonreciprocal and nonoverlapping gene expression changes in the central nervous system of Drosophila. G3 (Bethesda), 2, 789-802.
Huang, C., Tong, J., Bi, F., Zhou, H., and Xia, X.G. (2012). Mutant TDP-43 in motor neurons promotes the onset and progression of ALS in rats. J Clin Invest, 122, 107-118.
Huang, C.C., Bose, J.K., Majumder, P., Lee, K.H., Huang, J.T., Huang, J.K., and Shen, C.K. (2014). Metabolism and mis-metabolism of the neuropathological signature protein TDP-43. J Cell Sci, 127, 3024-3038.
Igaz, L.M., Kwong, L.K., Chen-Plotkin, A., Winton, M.J., Unger, T.L., Xu, Y., Neumann, M., Trojanowski, J.Q., and Lee, V.M. (2009). Expression of TDP-43 C-terminal Fragments in Vitro Recapitulates Pathological Features of TDP-43 Proteinopathies. J Biol Chem, 284, 8516-8524.
Igaz, L.M., Kwong, L.K., Lee, E.B., Chen-Plotkin, A., Swanson, E., Unger, T., Malunda, J., Xu, Y., Winton, M.J., Trojanowski, J.Q., et al. (2011). Dysregulation of the ALS-associated gene TDP-43 leads to neuronal death and degeneration in mice. J Clin Invest, 121, 726-738.
Iguchi, Y., Katsuno, M., Niwa, J., Takagi, S., Ishigaki, S., Ikenaka, K., Kawai, K., Watanabe, H., Yamanaka, K., Takahashi, R., et al. (2013). Loss of TDP-43 causes age-dependent progressive motor neuron degeneration. Brain, 136, 1371-1382.
Janssens, J., Wils, H., Kleinberger, G., Joris, G., Cuijt, I., Ceuterick-de Groote, C., Van Broeckhoven, C., and Kumar-Singh, S. (2013). Overexpression of ALS-associated p.M337V human TDP-43 in mice worsens disease features compared to wild-type human TDP-43 mice. Mol Neurobiol, 48, 22-35.
Joardar, A., Menzl, J., Podolsky, T.C., Manzo, E., Estes, P.S., Ashford, S., and Zarnescu, D.C. (2015). PPAR gamma activation is neuroprotective in a Drosophila model of ALS based on TDP-43. Hum Mol Genet, 24, 1741-1754.
Kasai, T., Tokuda, T., Ishigami, N., Sasayama, H., Foulds, P., Mitchell, D.J., Mann, D.M., Allsop, D., and Nakagawa, M. (2009). Increased TDP-43 protein in cerebrospinal fluid of patients with amyotrophic lateral sclerosis. Acta Neuropathol, 117, 55-62.
Kim, D.H., Sarbassov, D.D., Ali, S.M., King, J.E., Latek, R.R., Erdjument-Bromage, H., Tempst, P., and Sabatini, D.M. (2002). mTOR interacts with raptor to form a nutrient-sensitive complex that signals to the cell growth machinery. Cell, 110, 163-175.
Kim, H.J., Raphael, A.R., LaDow, E.S., McGurk, L., Weber, R.A., Trojanowski, J.Q., Lee, V.M., Finkbeiner, S., Gitler, A.D., and Bonini, N.M. (2014). Therapeutic modulation of eIF2alpha phosphorylation rescues TDP-43 toxicity in amyotrophic lateral sclerosis disease models. Nat Genet, 46, 152-160.
Kim, S.H., Shi, Y., Hanson, K.A., Williams, L.M., Sakasai, R., Bowler, M.J., and Tibbetts, R.S. (2009). Potentiation of amyotrophic lateral sclerosis (ALS)-associated TDP-43 aggregation by the proteasome-targeting factor, ubiquilin 1. J Biol Chem, 284, 8083-8092.
Kuo, P.H., Doudeva, L.G., Wang, Y.T., Shen, C.K., and Yuan, H.S. (2009). Structural insights into TDP-43 in nucleic-acid binding and domain interactions. Nucleic Acids Res, 37, 1799-1808.
Lalmansingh, A.S., Urekar, C.J., and Reddi, P.P. (2011). TDP-43 is a transcriptional repressor: the testis-specific mouse acrv1 gene is a TDP-43 target in vivo. J Biol Chem, 286, 10970-10982.
Laplante, M., and Sabatini, D.M. (2012). mTOR signaling in growth control and disease. Cell, 149, 274-293.
Lattante, S., Rouleau, G.A., and Kabashi, E. (2013). TARDBP and FUS mutations associated with amyotrophic lateral sclerosis: summary and update. Hum Mutat, 34, 812-826.
Lee, T., Lee, A., and Luo, L. (1999). Development of the Drosophila mushroom bodies: sequential generation of three distinct types of neurons from a neuroblast. Development, 126, 4065-4076.
Li, Y., Ray, P., Rao, E.J., Shi, C., Guo, W., Chen, X., Woodruff, E.A., 3rd, Fushimi, K., and Wu, J.Y. (2010). A Drosophila model for TDP-43 proteinopathy. Proc Natl Acad Sci U S A, 107, 3169-3174.
Li, Z., Lu, Y., Xu, X.L., and Gao, F.B. (2013). The FTD/ALS-associated RNA-binding protein TDP-43 regulates the robustness of neuronal specification through microRNA-9a in Drosophila. Hum Mol Genet, 22, 218-225.
Liachko, N.F., Guthrie, C.R., and Kraemer, B.C. (2010). Phosphorylation promotes neurotoxicity in a Caenorhabditis elegans model of TDP-43 proteinopathy. J Neurosci, 30, 16208-16219.
Lin, M.J., Cheng, C.W., and Shen, C.K. (2011). Neuronal function and dysfunction of Drosophila dTDP. PLoS One, 6, e20371.
Ling, S.C., Albuquerque, C.P., Han, J.S., Lagier-Tourenne, C., Tokunaga, S., Zhou, H., and Cleveland, D.W. (2010). ALS-associated mutations in TDP-43 increase its stability and promote TDP-43 complexes with FUS/TLS. Proc Natl Acad Sci U S A, 107, 13318-13323.
Ling, S.C., Polymenidou, M., and Cleveland, D.W. (2013). Converging mechanisms in ALS and FTD: disrupted RNA and protein homeostasis. Neuron, 79, 416-438.
Liscic, R.M., Grinberg, L.T., Zidar, J., Gitcho, M.A., and Cairns, N.J. (2008). ALS and FTLD: two faces of TDP-43 proteinopathy. Eur J Neurol, 15, 772-780.
Logroscino, G., Traynor, B.J., Hardiman, O., Chio, A., Mitchell, D., Swingler, R.J., Millul, A., Benn, E., and Beghi, E. (2010). Incidence of amyotrophic lateral sclerosis in Europe. J Neurol Neurosurg Psychiatry, 81, 385-390.
Lu, Y., Ferris, J., and Gao, F.B. (2009). Frontotemporal dementia and amyotrophic lateral sclerosis-associated disease protein TDP-43 promotes dendritic branching. Mol Brain, 2, 30.
Mackenzie, I.R., Bigio, E.H., Ince, P.G., Geser, F., Neumann, M., Cairns, N.J., Kwong, L.K., Forman, M.S., Ravits, J., Stewart, H., et al. (2007). Pathological TDP-43 distinguishes sporadic amyotrophic lateral sclerosis from amyotrophic lateral sclerosis with SOD1 mutations. Ann Neurol, 61, 427-434.
Mackenzie, I.R., Rademakers, R., and Neumann, M. (2010). TDP-43 and FUS in amyotrophic lateral sclerosis and frontotemporal dementia. Lancet Neurol, 9, 995-1007.
McDonald, K.K., Aulas, A., Destroismaisons, L., Pickles, S., Beleac, E., Camu, W., Rouleau, G.A., and Vande Velde, C. (2011). TAR DNA-binding protein 43 (TDP-43) regulates stress granule dynamics via differential regulation of G3BP and TIA-1. Hum Mol Genet, 20, 1400-1410.
Mercado, P.A., Ayala, Y.M., Romano, M., Buratti, E., and Baralle, F.E. (2005). Depletion of TDP 43 overrides the need for exonic and intronic splicing enhancers in the human apoA-II gene. Nucleic Acids Res, 33, 6000-6010.
Mishra, M., Paunesku, T., Woloschak, G.E., Siddique, T., Zhu, L.J., Lin, S., Greco, K., and Bigio, E.H. (2007). Gene expression analysis of frontotemporal lobar degeneration of the motor neuron disease type with ubiquitinated inclusions. Acta Neuropathol, 114, 81-94.
Mizushima, N., Levine, B., Cuervo, A.M., and Klionsky, D.J. (2008). Autophagy fights disease through cellular self-digestion. Nature, 451, 1069-1075.
Neumann, M., Sampathu, D.M., Kwong, L.K., Truax, A.C., Micsenyi, M.C., Chou, T.T., Bruce, J., Schuck, T., Grossman, M., Clark, C.M., et al. (2006). Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Science, 314, 130-133.
Odden, J.P., Holbrook, S., and Doe, C.Q. (2002). Drosophila HB9 is expressed in a subset of motoneurons and interneurons, where it regulates gene expression and axon pathfinding. J Neurosci, 22, 9143-9149.
Ou, S.H., Wu, F., Harrich, D., Garcia-Martinez, L.F., and Gaynor, R.B. (1995). Cloning and characterization of a novel cellular protein, TDP-43, that binds to human immunodeficiency virus type 1 TAR DNA sequence motifs. J Virol, 69, 3584-3596.
Pircs, K., Nagy, P., Varga, A., Venkei, Z., Erdi, B., Hegedus, K., and Juhasz, G. (2012). Advantages and limitations of different p62-based assays for estimating autophagic activity in Drosophila. PLoS One, 7, e44214.
Polymenidou, M., Lagier-Tourenne, C., Hutt, K.R., Huelga, S.C., Moran, J., Liang, T.Y., Ling, S.C., Sun, E., Wancewicz, E., Mazur, C., et al. (2011). Long pre-mRNA depletion and RNA missplicing contribute to neuronal vulnerability from loss of TDP-43. Nat Neurosci, 14, 459-468.
Ravikumar, B., Vacher, C., Berger, Z., Davies, J.E., Luo, S., Oroz, L.G., Scaravilli, F., Easton, D.F., Duden, R., O''Kane, C.J., et al. (2004). Inhibition of mTOR induces autophagy and reduces toxicity of polyglutamine expansions in fly and mouse models of Huntington disease. Nat Genet, 36, 585-595.
Renton, A.E., Chio, A., and Traynor, B.J. (2014). State of play in amyotrophic lateral sclerosis genetics. Nat Neurosci, 17, 17-23.
Rieger, D., Shafer, O.T., Tomioka, K., and Helfrich-Forster, C. (2006). Functional analysis of circadian pacemaker neurons in Drosophila melanogaster. J Neurosci, 26, 2531-2543.
Rowland, L.P., and Shneider, N.A. (2001). Amyotrophic lateral sclerosis. N Engl J Med, 344, 1688-1700.
Rubinsztein, D.C., Codogno, P., and Levine, B. (2012). Autophagy modulation as a potential therapeutic target for diverse diseases. Nat Rev Drug Discov, 11, 709-730.
Salado, I.G., Redondo, M., Bello, M.L., Perez, C., Liachko, N.F., Kraemer, B.C., Miguel, L., Lecourtois, M., Gil, C., Martinez, A., et al. (2014). Protein kinase CK-1 inhibitors as new potential drugs for amyotrophic lateral sclerosis. J Med Chem, 57, 2755-2772.
Sarkar, S., Perlstein, E.O., Imarisio, S., Pineau, S., Cordenier, A., Maglathlin, R.L., Webster, J.A., Lewis, T.A., O''Kane, C.J., Schreiber, S.L., et al. (2007). Small molecules enhance autophagy and reduce toxicity in Huntington''s disease models. Nat Chem Biol, 3, 331-338.
Sephton, C.F., Good, S.K., Atkin, S., Dewey, C.M., Mayer, P., 3rd, Herz, J., and Yu, G. (2010). TDP-43 is a developmentally regulated protein essential for early embryonic development. J Biol Chem, 285, 6826-6834.
Spilman, P., Podlutskaya, N., Hart, M.J., Debnath, J., Gorostiza, O., Bredesen, D., Richardson, A., Strong, R., and Galvan, V. (2010). Inhibition of mTOR by rapamycin abolishes cognitive deficits and reduces amyloid-beta levels in a mouse model of Alzheimer''s disease. PLoS One, 5, e9979.
Strong, M.J., Volkening, K., Hammond, R., Yang, W., Strong, W., Leystra-Lantz, C., and Shoesmith, C. (2007). TDP43 is a human low molecular weight neurofilament (hNFL) mRNA-binding protein. Mol Cell Neurosci, 35, 320-327.
Tatom, J.B., Wang, D.B., Dayton, R.D., Skalli, O., Hutton, M.L., Dickson, D.W., and Klein, R.L. (2009). Mimicking aspects of frontotemporal lobar degeneration and Lou Gehrig''s disease in rats via TDP-43 overexpression. Mol Ther, 17, 607-613.
Tollervey, J.R., Curk, T., Rogelj, B., Briese, M., Cereda, M., Kayikci, M., Konig, J., Hortobagyi, T., Nishimura, A.L., Zupunski, V., et al. (2011). Characterizing the RNA targets and position-dependent splicing regulation by TDP-43. Nat Neurosci, 14, 452-458.
Tooze, S.A., and Schiavo, G. (2008). Liaisons dangereuses: autophagy, neuronal survival and neurodegeneration. Curr Opin Neurobiol, 18, 504-515.
Tsai, K.J., Yang, C.H., Fang, Y.H., Cho, K.H., Chien, W.L., Wang, W.T., Wu, T.W., Lin, C.P., Fu, W.M., and Shen, C.K. (2010a). Elevated expression of TDP-43 in the forebrain of mice is sufficient to cause neurological and pathological phenotypes mimicking FTLD-U. J Exp Med, 207, 1661-1673.
Tsai, K.J., Yang, C.H., Fang, Y.H., Cho, K.H., Chien, W.L., Wang, W.T., Wu, T.W., Lin, C.P., Fu, W.M., and Shen, C.K. (2010b). Elevated expression of TDP-43 in the forebrain of mice is sufficient to cause neurological and pathological phenotypes mimicking FTLD-U. J Exp Med, 207, 1661-1673.
Tully, T., and Quinn, W.G. (1985). Classical conditioning and retention in normal and mutant Drosophila melanogaster. J Comp Physiol, 157, 263-277.
Uchida, A., Sasaguri, H., Kimura, N., Tajiri, M., Ohkubo, T., Ono, F., Sakaue, F., Kanai, K., Hirai, T., Sano, T., et al. (2012). Non-human primate model of amyotrophic lateral sclerosis with cytoplasmic mislocalization of TDP-43. Brain, 135, 833-846.
Vaccaro, A., Tauffenberger, A., Aggad, D., Rouleau, G., Drapeau, P., and Parker, J.A. (2012). Mutant TDP-43 and FUS cause age-dependent paralysis and neurodegeneration in C. elegans. PLoS One, 7, e31321.
Van Langenhove, T., van der Zee, J., and Van Broeckhoven, C. (2012). The molecular basis of the frontotemporal lobar degeneration-amyotrophic lateral sclerosis spectrum. Ann Med, 44, 817-828.
Voigt, A., Herholz, D., Fiesel, F.C., Kaur, K., Muller, D., Karsten, P., Weber, S.S., Kahle, P.J., Marquardt, T., and Schulz, J.B. (2010). TDP-43-mediated neuron loss in vivo requires RNA-binding activity. PLoS One, 5, e12247.
Waddell, S., and Quinn, W.G. (2001). Flies, genes, and learning. Annu Rev Neurosci, 24, 1283-1309.
Wang, H.Y., Wang, I.F., Bose, J., and Shen, C.K. (2004). Structural diversity and functional implications of the eukaryotic TDP gene family. Genomics, 83, 130-139.
Wang, I.F., Guo, B.S., Liu, Y.C., Wu, C.C., Yang, C.H., Tsai, K.J., and Shen, C.K. (2012). Autophagy activators rescue and alleviate pathogenesis of a mouse model with proteinopathies of the TAR DNA-binding protein 43. Proc Natl Acad Sci U S A, 109, 15024-15029.
Wang, I.F., Tsai, K.J., and Shen, C.K. (2013). Autophagy activation ameliorates neuronal pathogenesis of FTLD-U mice: a new light for treatment of TARDBP/TDP-43 proteinopathies. Autophagy, 9, 239-240.
Wang, I.F., Wu, L.S., Chang, H.Y., and Shen, C.K. (2008). TDP-43, the signature protein of FTLD-U, is a neuronal activity-responsive factor. J Neurochem, 105, 797-806.
Watson, M.R., Lagow, R.D., Xu, K., Zhang, B., and Bonini, N.M. (2008). A drosophila model for amyotrophic lateral sclerosis reveals motor neuron damage by human SOD1. J Biol Chem, 283, 24972-24981.
Wegorzewska, I., Bell, S., Cairns, N.J., Miller, T.M., and Baloh, R.H. (2009). TDP-43 mutant transgenic mice develop features of ALS and frontotemporal lobar degeneration. Proc Natl Acad Sci U S A, 106, 18809-18814.
Wils, H., Kleinberger, G., Janssens, J., Pereson, S., Joris, G., Cuijt, I., Smits, V., Ceuterick-de Groote, C., Van Broeckhoven, C., and Kumar-Singh, S. (2010). TDP-43 transgenic mice develop spastic paralysis and neuronal inclusions characteristic of ALS and frontotemporal lobar degeneration. Proc Natl Acad Sci U S A, 107, 3858-3863.
Winton, M.J., Igaz, L.M., Wong, M.M., Kwong, L.K., Trojanowski, J.Q., and Lee, V.M. (2008). Disturbance of nuclear and cytoplasmic TAR DNA-binding protein (TDP-43) induces disease-like redistribution, sequestration, and aggregate formation. J Biol Chem, 283, 13302-13309.
Wu, L.S., Cheng, W.C., Hou, S.C., Yan, Y.T., Jiang, S.T., and Shen, C.K. (2010). TDP-43, a neuro-pathosignature factor, is essential for early mouse embryogenesis. Genesis, 48, 56-62.
Wu, L.S., Cheng, W.C., and Shen, C.K. (2012). Targeted depletion of TDP-43 expression in the spinal cord motor neurons leads to the development of amyotrophic lateral sclerosis-like phenotypes in mice. J Biol Chem, 287, 27335-27344.
Xu, Y.F., Gendron, T.F., Zhang, Y.J., Lin, W.L., D''Alton, S., Sheng, H., Casey, M.C., Tong, J., Knight, J., Yu, X., et al. (2010). Wild-type human TDP-43 expression causes TDP-43 phosphorylation, mitochondrial aggregation, motor deficits, and early mortality in transgenic mice. J Neurosci, 30, 10851-10859.
Zars, T., Fischer, M., Schulz, R., and Heisenberg, M. (2000). Localization of a short-term memory in Drosophila. Science, 288, 672-675.
Zhang, X., Li, L., Chen, S., Yang, D., Wang, Y., Wang, Z., and Le, W. (2011). Rapamycin treatment augments motor neuron degeneration in SOD1(G93A) mouse model of amyotrophic lateral sclerosis. Autophagy, 7, 412-425.
Zhang, Y.J., Xu, Y.F., Cook, C., Gendron, T.F., Roettges, P., Link, C.D., Lin, W.L., Tong, J., Castanedes-Casey, M., Ash, P., et al. (2009). Aberrant cleavage of TDP-43 enhances aggregation and cellular toxicity. Proc Natl Acad Sci U S A, 106, 7607-7612.
Zhou, H., Huang, C., Chen, H., Wang, D., Landel, C.P., Xia, P.Y., Bowser, R., Liu, Y.J., and Xia, X.G. (2010). Transgenic rat model of neurodegeneration caused by mutation in the TDP gene. PLoS Genet, 6, e1000887.





QRCODE
 
 
 
 
 
                                                                                                                                                                                                                                                                                                                                                                                                               
第一頁 上一頁 下一頁 最後一頁 top
無相關點閱論文