簡易檢索 / 詳目顯示

回結果列表
研究生： 曾秀珍
Chan, Siew Chin
論文名稱： 探討染色體9號開放讀序框架72在亨丁頓氏症的角色
Investigating the roles of Chromosome 9 open reading frame 72 in Huntington's Disease
指導教授： 楊尚訓
Yang, Shang-Hsun
學位類別： 碩士
Master
系所名稱： 醫學院 - 生理學研究所
Department of Physiology
論文出版年： 2021
畢業學年度： 109
語文別： 英文
論文頁數： 89
中文關鍵詞： 亨丁頓式舞蹈症 、染色體9號開放讀序框架72 蛋白 、自噬系統 、泛素-蛋白酶體系統 、神經元傳輸系統
外文關鍵詞： Huntington’s Disease, C9orf72, Autophagy, Ubiquitin-proteasome system, Neuronal transport
相關次數： 點閱：78  下載：0 
分享至:
查詢本校圖書館目錄 查詢臺灣博碩士論文知識加值系統 勘誤回報

    • 亨丁頓式舞蹈症（Huntington’s disease， HD）為一種遺傳性神經退化疾病，由亨廷頓基因（Huntingtin, HTT）外顯子1（exon 1）的CAG重複擴增引起，導致細胞內不正常堆積突變蛋白進而造成神經退化。蛋白質降解系統和神經元傳輸系統對於神經元的維持和功能至關重要，這些途徑的破壞將導致神經退化性疾病。過去已發現染色體9號開放讀序框架72 蛋白（C9orf72）參與在這些途徑當中，並且C9orf72的突變也被參與在好幾種神經退化性疾病當中。然而，野生型C9orf72在HD中的作用仍不清楚。本研究的目標旨在研究C9orf72在HD中的影響。首先，我們通過生物資訊分析發現，HD患者血液樣本中C9orf72的表現量與正常人相比是較高的，並且在HD基因轉殖小鼠中觀察到相似的結果。接下來，我們發現C9orf72的過表達誘導了突變HTT聚集體的形成，但不會在神經母細胞瘤-2a（N2a）細胞中引起神經毒性。此外，我們發現C9orf72的過表達不影響自噬系統（autophagy）和 泛素-蛋白酶體系統（ubiquitin-proteasome system; UPS）。因此，我們進一步分析了軸突運輸的功能，並證明C9orf72會損害神經元的運輸。最後，我們也成功建立了C9orf72基因轉殖小鼠。同時，我們將C9orf72慢病毒立體定位注射到HD小鼠的紋狀體區域中，並發現C9orf72在紋狀體區域中有造成突變HTT增加的趨勢。綜合上述結果，我們的研究證明C9orf72誘導突變HTT聚集並導致軸突運輸功能的障礙。在我們未來的計劃中，我們希望可以更進一步瞭解C9orf72在神經元運輸的詳細機制，並會繼續建立 C9orf72-HD 雙基因轉殖小鼠，以便進一步分析C9orf72在活體對HD的影響。我們預計這項研究將更加瞭解致病過程，並為該疾病提供新的治療方向。

    Huntington’s disease (HD) is an inherited neurodegenerative disorder and caused by CAG repeat expansions at exon 1 of the huntingtin (HTT) gene that results in intracellular aggregate formations and neurodegeneration. Protein degradation systems and neuronal transports are crucial for the maintenance and functions of a neuron, and the impairments of these functions have been observed in neurological diseases. Chromosome 9 open reading frame 72 (C9orf72) has been found to be involved in those functions, and the mutation of C9orf72 is observed in several neurodegenerative diseases. However, the role of wild-type C9orf72 in HD is still unclear. The goal of this study aims to investigate the effects of C9orf72 in HD models. Here, we found that the expression level of C9orf72 was higher in blood samples of HD patients compared to those of normal people via bioinformatic analyses, and similar results were observed in HD transgenic mice. Next, we found that overexpression of C9orf72 induced mHTT aggregate formations ,but did not cause neurotoxicity in N2a cells. . Furthermore, we found overexpression of C9orf72 did not affect the autophagy and ubiquitin–proteasome systems. Thus, we further analyzed the functions of axonal transport, and showed that C9orf72 impaired the neuronal transportation. Finally, we generated the C9orf72 transgenic mice. At the same time, we used stereotaxical injection of C9orf72 lentiviruses into the brains of the HD mouse model and observed C9orf72 causes a tendency of increased mHTT in striatum regions. In summary, our studies showed that C9orf72 induced mHTT aggregates and led to axonal transport dysfunctions. In our future work, we will not only address on the detailed mechanisms of neuronal transportation, but also generate the C9orf72-HD double transgenic mice for further analyses related to HD phenotypes in vivo. We anticipate that this study will shed light on the entire disease process and provide the novel therapy for the disease.

    Abstract I 中文摘要 II Acknowledgements III Contents IV Figure Contents VII Chapter 1: Introduction 1 1.1 Background of Huntington’s disease 1 1.2 Huntingtin Protein 2 1.3 Therapeutic in HD 2 1.4 Protein biogenesis and degradation 3 1.5 Ubiquitin proteasome system (UPS) 4 1.6 Autophagy 5 1.7 Impaired protein degradation pathways in HD 6 1.8 Neuronal transportation 6 1.9 Impairment of neuronal transportation in HD 7 1.10 Chromosome 9 open reading frame 72 (C9orf72) 8 1.11 The roles of C9orf72 in protein degradation pathways and neuronal transportations 8 Chapter 2: Objectives and Specific Aims 10 Chapter 3: Materials and Methods 11 3.1 DNA plasmid construction 11 3.2 DNA transformation 13 3.3 DNA extraction 13 3.4 N2a cell culture 14 3.5 Subculture of N2a cells 14 3.6 Cells freezing and thawing 15 3.7 Transfection and Differentiation 16 3.8 Lentiviruses preparation 16 3.9 Generation of transgenic mice 17 3.10 Genotyping for transgenic mice 17 3.11 Reverse transcript PCR 18 3.12 Culture of primary neurons 19 3.13 Western blotting analysis 21 3.14 Trypan Blue Staining 25 3.15 Proteosome activity assay 26 3.16 Live cell imaging 26 3.17 Stereotactic viral injection 27 3.18 Behavioral tests 28 3.19 Preparation of mouse brain for histological analysis 29 3.20 Statistical analysis 30 Chapter 4: Results 31 4.1 C9orf72 is upregulated in Huntington’s Disease 31 4.2 Overexpressing C9orf72 induces mHTT aggregate formation 32 4.3 C9orf72 does not affect protein degradation systems 32 4.4 C9orf72 leads to deficits in neuronal transports 33 4.5 C9orf72 transgenic mice are generated 35 4.6 Stereotaxical injections of C9orf72 lentiviruses into HD mouse striatum have no effect on motor functions and mHTT aggregates 35 4.7 Stereotaxical injections of FUG84Q lentiviruses into C9orf72 transgenic mouse striatum do not cause motor function deficit 36 Chapter 5: Discussion 38 Chapter 6: Conclusion 43 Chapter 7: References 44 Chapter 8: Figures 58 Fig. 1) C9orf72 is upregulated in Huntington’s Disease. 59 Fig. 2) Overexpressing C9orf72 induces mHTT aggregate formation. 62 Fig. 3) C9orf72 does not affect the autophagy pathway. 64 Fig. 4) C9orf72 does not affect ubiquitin proteasome systems. 66 Fig. 5) C9orf72 leads to deficits in neuronal transport in N2a cells. 69 Fig. 6) C9orf72 does not affect neuronal transports in primary neurons. 72 Fig. 7) C9orf72 does not affect expressions of synaptic markers. 74 Fig. 8) C9orf72 transgenic mice are generated. 77 Fig. 9) The C9orf72-HD double transgenic mice have not been generated. 79 Fig. 10) Stereotaxical injections of C9orf72 lentiviruses into HD mouse striatum have no effect on motor functions. 83 Fig. 11) Stereotaxical injections of C9orf72 lentiviruses into HD mouse striatum have no effect on mHTT aggregates. 85 Fig. 12) Stereotaxical injections of FUG84Q lentiviruses into C9orf72 transgenic mouse striatum do not cause motor function deficit. 88 Fig. 13) Graphical abstract. 89

    1. Andresen, J. M., J. Gayan, L. Djousse, S. Roberts, D. Brocklebank, S. S. Cherny, U. S.-V. C. R. Group, H. M. C. R. Group, L. R. Cardon, J. F. Gusella, M. E. MacDonald, R. H. Myers, D. E. Housman and N. S. Wexler (2007). "The relationship between CAG repeat length and age of onset differs for Huntington's disease patients with juvenile onset or adult onset." Ann Hum Genet 71(Pt 3): 295-301.
    2. Bai, F. and F. A. Witzmann (2007). "Synaptosome proteomics." Subcell Biochem 43: 77-98.
    3. Baldwin, K. R., V. K. Godena, V. L. Hewitt and A. J. Whitworth (2016). "Axonal transport defects are a common phenotype in Drosophila models of ALS." Hum Mol Genet 25(12): 2378-2392.
    4. Bates, G. P., R. Dorsey, J. F. Gusella, M. R. Hayden, C. Kay, B. R. Leavitt, M. Nance, C. A. Ross, R. I. Scahill, R. Wetzel, E. J. Wild and S. J. Tabrizi (2015). "Huntington disease." Nat Rev Dis Primers 1: 15005.
    5. Bennett, E. J., T. A. Shaler, B. Woodman, K. Y. Ryu, T. S. Zaitseva, C. H. Becker, G. P. Bates, H. Schulman and R. R. Kopito (2007). "Global changes to the ubiquitin system in Huntington's disease." Nature 448(7154): 704-708.
    6. Bucci, C., P. Alifano and L. Cogli (2014). "The role of rab proteins in neuronal cells and in the trafficking of neurotrophin receptors." Membranes (Basel) 4(4): 642-677.
    7. Button, R. W., S. Luo and D. C. Rubinsztein (2015). "Autophagic activity in neuronal cell death." Neurosci Bull 31(4): 382-394.
    8. Cali, C. P., M. Patino, Y. K. Tai, W. Y. Ho, C. A. McLean, C. M. Morris, W. W. Seeley, B. L. Miller, C. Gaig, J. P. G. Vonsattel, C. L. White, 3rd, S. Roeber, H. Kretzschmar, J. C. Troncoso, C. Troakes, M. Gearing, B. Ghetti, V. M. Van Deerlin, V. M. Lee, J. Q. Trojanowski, K. Y. Mok, H. Ling, D. W. Dickson, G. D. Schellenberg, S. C. Ling and E. B. Lee (2019). "C9orf72 intermediate repeats are associated with corticobasal degeneration, increased C9orf72 expression and disruption of autophagy." Acta Neuropathol 138(5): 795-811.
    9. Caron, N. S., E. R. Dorsey and M. R. Hayden (2018). "Therapeutic approaches to Huntington disease: from the bench to the clinic." Nat Rev Drug Discov 17(10): 729-750.
    10. Cattaneo, E., C. Zuccato and M. Tartari (2005). "Normal huntingtin function: an alternative approach to Huntington's disease." Nat Rev Neurosci 6(12): 919-930.
    11. Cheng, P. H., C. L. Li, L. S. Her, Y. F. Chang, A. W. Chan, C. M. Chen and S. H. Yang (2013). "Significantly differential diffusion of neuropathological aggregates in the brain of transgenic mice carrying N-terminal mutant huntingtin fused with green fluorescent protein." Brain Struct Funct 218(1): 283-294.
    12. Chitiprolu, M., C. Jagow, V. Tremblay, E. Bondy-Chorney, G. Paris, A. Savard, G. Palidwor, F. A. Barry, L. Zinman, J. Keith, E. Rogaeva, J. Robertson, M. Lavallee-Adam, J. Woulfe, J. F. Couture, J. Cote and D. Gibbings (2018). "A complex of C9ORF72 and p62 uses arginine methylation to eliminate stress granules by autophagy." Nat Commun 9(1): 2794.
    13. Cooper, J. K., G. Schilling, M. F. Peters, W. J. Herring, A. H. Sharp, Z. Kaminsky, J. Masone, F. A. Khan, M. Delanoy, D. R. Borchelt, V. L. Dawson, T. M. Dawson and C. A. Ross (1998). "Truncated N-terminal fragments of huntingtin with expanded glutamine repeats form nuclear and cytoplasmic aggregates in cell culture." Hum Mol Genet 7(5): 783-790.
    14. Dabrowska, M., W. Juzwa, W. J. Krzyzosiak and M. Olejniczak (2018). "Precise Excision of the CAG Tract from the Huntingtin Gene by Cas9 Nickases." Front Neurosci 12: 75.
    15. De Vos, K. J., A. J. Grierson, S. Ackerley and C. C. Miller (2008). "Role of axonal transport in neurodegenerative diseases." Annu Rev Neurosci 31: 151-173.
    16. DiFiglia, M., M. Sena-Esteves, K. Chase, E. Sapp, E. Pfister, M. Sass, J. Yoder, P. Reeves, R. K. Pandey, K. G. Rajeev, M. Manoharan, D. W. Sah, P. D. Zamore and N. Aronin (2007). "Therapeutic silencing of mutant huntingtin with siRNA attenuates striatal and cortical neuropathology and behavioral deficits." Proc Natl Acad Sci U S A 104(43): 17204-17209.
    17. Engelender, S., A. H. Sharp, V. Colomer, M. K. Tokito, A. Lanahan, P. Worley, E. L. Holzbaur and C. A. Ross (1997). "Huntingtin-associated protein 1 (HAP1) interacts with the p150Glued subunit of dynactin." Hum Mol Genet 6(13): 2205-2212.
    18. Farg, M. A., V. Sundaramoorthy, J. M. Sultana, S. Yang, R. A. Atkinson, V. Levina, M. A. Halloran, P. A. Gleeson, I. P. Blair, K. Y. Soo, A. E. King and J. D. Atkin (2014). "C9ORF72, implicated in amytrophic lateral sclerosis and frontotemporal dementia, regulates endosomal trafficking." Hum Mol Genet 23(13): 3579-3595.
    19. Feng, Y., D. He, Z. Yao and D. J. Klionsky (2014). "The machinery of macroautophagy." Cell Res 24(1): 24-41.
    20. Fink, K. D., P. Deng, J. Gutierrez, J. S. Anderson, A. Torrest, A. Komarla, S. Kalomoiris, W. Cary, J. D. Anderson, W. Gruenloh, A. Duffy, T. Tempkin, G. Annett, V. Wheelock, D. J. Segal and J. A. Nolta (2016). "Allele-Specific Reduction of the Mutant Huntingtin Allele Using Transcription Activator-Like Effectors in Human Huntington's Disease Fibroblasts." Cell Transplant 25(4): 677-686.
    21. Frick, P., C. Sellier, I. R. A. Mackenzie, C. Y. Cheng, J. Tahraoui-Bories, C. Martinat, R. J. Pasterkamp, J. Prudlo, D. Edbauer, M. Oulad-Abdelghani, R. Feederle, N. Charlet-Berguerand and M. Neumann (2018). "Novel antibodies reveal presynaptic localization of C9orf72 protein and reduced protein levels in C9orf72 mutation carriers." Acta Neuropathol Commun 6(1): 72.
    22. Garriga-Canut, M., C. Agustin-Pavon, F. Herrmann, A. Sanchez, M. Dierssen, C. Fillat and M. Isalan (2012). "Synthetic zinc finger repressors reduce mutant huntingtin expression in the brain of R6/2 mice." Proc Natl Acad Sci U S A 109(45): E3136-3145.
    23. Gebauer, F. and M. W. Hentze (2004). "Molecular mechanisms of translational control." Nat Rev Mol Cell Biol 5(10): 827-835.
    24. Geronimo-Olvera, C. and L. Massieu (2019). "Autophagy as a Homeostatic Mechanism in Response to Stress Conditions in the Central Nervous System." Mol Neurobiol 56(9): 6594-6608.
    25. Ghosh, R. and S. J. Tabrizi (2018). "Clinical Features of Huntington's Disease." Adv Exp Med Biol 1049: 1-28.
    26. Glasgow, S. D., R. McPhedrain, J. F. Madranges, T. E. Kennedy and E. S. Ruthazer (2019). "Approaches and Limitations in the Investigation of Synaptic Transmission and Plasticity." Front Synaptic Neurosci 11: 20.
    27. Guedes-Dias, P. and E. L. F. Holzbaur (2019). "Axonal transport: Driving synaptic function." Science 366(6462).
    28. Gunawardena, S., L. S. Her, R. G. Brusch, R. A. Laymon, I. R. Niesman, B. Gordesky-Gold, L. Sintasath, N. M. Bonini and L. S. Goldstein (2003). "Disruption of axonal transport by loss of huntingtin or expression of pathogenic polyQ proteins in Drosophila." Neuron 40(1): 25-40.
    29. Harper, S. Q., P. D. Staber, X. He, S. L. Eliason, I. H. Martins, Q. Mao, L. Yang, R. M. Kotin, H. L. Paulson and B. L. Davidson (2005). "RNA interference improves motor and neuropathological abnormalities in a Huntington's disease mouse model." Proc Natl Acad Sci U S A 102(16): 5820-5825.
    30. Haruyama, N., A. Cho and A. B. Kulkarni (2009). "Overview: engineering transgenic constructs and mice." Curr Protoc Cell Biol Chapter 19: Unit 19 10.
    31. Heemskerk, A. W. and R. A. Roos (2012). "Aspiration pneumonia and death in Huntington's disease." PLoS Curr 4: RRN1293.
    32. Hensman Moss, D. J., M. Poulter, J. Beck, J. Hehir, J. M. Polke, T. Campbell, G. Adamson, E. Mudanohwo, P. McColgan, A. Haworth, E. J. Wild, M. G. Sweeney, H. Houlden, S. Mead and S. J. Tabrizi (2014). "C9orf72 expansions are the most common genetic cause of Huntington disease phenocopies." Neurology 82(4): 292-299.
    33. Hirokawa, N. (1998). "Kinesin and dynein superfamily proteins and the mechanism of organelle transport." Science 279(5350): 519-526.
    34. Hirokawa, N. and R. Takemura (2005). "Molecular motors and mechanisms of directional transport in neurons." Nat Rev Neurosci 6(3): 201-214.
    35. Ida, C. M., M. L. Butz, P. A. Lundquist and D. B. Dawson (2018). "C9orf72 Repeat Expansion Frequency among Patients with Huntington Disease Genetic Testing." Neurodegener Dis 18(5-6): 239-253.
    36. Ittner, L. M. and J. Gotz (2007). "Pronuclear injection for the production of transgenic mice." Nat Protoc 2(5): 1206-1215.
    37. Jimenez-Sanchez, M., F. Licitra, B. R. Underwood and D. C. Rubinsztein (2017). "Huntington's Disease: Mechanisms of Pathogenesis and Therapeutic Strategies." Cold Spring Harb Perspect Med 7(7).
    38. Jordens, I., M. Marsman, C. Kuijl and J. Neefjes (2005). "Rab proteins, connecting transport and vesicle fusion." Traffic 6(12): 1070-1077.
    39. Joseph, B. K., K. M. Thakali, A. R. Pathan, E. Kang, N. J. Rusch and S. W. Rhee (2011). "Postsynaptic density-95 scaffolding of Shaker-type K(+) channels in smooth muscle cells regulates the diameter of cerebral arteries." J Physiol 589(Pt 21): 5143-5152.
    40. Kaether, C., P. Skehel and C. G. Dotti (2000). "Axonal membrane proteins are transported in distinct carriers: a two-color video microscopy study in cultured hippocampal neurons." Mol Biol Cell 11(4): 1213-1224.
    41. Kiral, F. R., F. E. Kohrs, E. J. Jin and P. R. Hiesinger (2018). "Rab GTPases and Membrane Trafficking in Neurodegeneration." Curr Biol 28(8): R471-R486.
    42. Kisselev, A. F., A. Callard and A. L. Goldberg (2006). "Importance of the different proteolytic sites of the proteasome and the efficacy of inhibitors varies with the protein substrate." J Biol Chem 281(13): 8582-8590.
    43. Kleiger, G. and T. Mayor (2014). "Perilous journey: a tour of the ubiquitin-proteasome system." Trends Cell Biol 24(6): 352-359.
    44. Kordasiewicz, H. B., L. M. Stanek, E. V. Wancewicz, C. Mazur, M. M. McAlonis, K. A. Pytel, J. W. Artates, A. Weiss, S. H. Cheng, L. S. Shihabuddin, G. Hung, C. F. Bennett and D. W. Cleveland (2012). "Sustained therapeutic reversal of Huntington's disease by transient repression of huntingtin synthesis." Neuron 74(6): 1031-1044.
    45. Koutsis, G., G. Karadima, C. Kartanou, A. Kladi and M. Panas (2015). "C9ORF72 hexanucleotide repeat expansions are a frequent cause of Huntington disease phenocopies in the Greek population." Neurobiol Aging 36(1): 547 e513-546.
    46. Kroemer, G. and B. Levine (2008). "Autophagic cell death: the story of a misnomer." Nat Rev Mol Cell Biol 9(12): 1004-1010.
    47. Labbadia, J. and R. I. Morimoto (2013). "Huntington's disease: underlying molecular mechanisms and emerging concepts." Trends Biochem Sci 38(8): 378-385.
    48. Lee, D., T. H. Huang, A. De La Cruz, A. Callejas and C. Lois (2017). "Methods to investigate the structure and connectivity of the nervous system." Fly (Austin) 11(3): 224-238.
    49. Lee, W. C., M. Yoshihara and J. T. Littleton (2004). "Cytoplasmic aggregates trap polyglutamine-containing proteins and block axonal transport in a Drosophila model of Huntington's disease." Proc Natl Acad Sci U S A 101(9): 3224-3229.
    50. Leskela, S., N. Huber, H. Rostalski, T. Natunen, A. M. Remes, M. Takalo, M. Hiltunen and A. Haapasalo (2019). "C9orf72 Proteins Regulate Autophagy and Undergo Autophagosomal or Proteasomal Degradation in a Cell Type-Dependent Manner." Cells 8(10).
    51. Levine, T. P., R. D. Daniels, A. T. Gatta, L. H. Wong and M. J. Hayes (2013). "The product of C9orf72, a gene strongly implicated in neurodegeneration, is structurally related to DENN Rab-GEFs." Bioinformatics 29(4): 499-503.
    52. Li, J. Y., N. Popovic and P. Brundin (2005). "The use of the R6 transgenic mouse models of Huntington's disease in attempts to develop novel therapeutic strategies." NeuroRx 2(3): 447-464.
    53. Li, W., T. Nie, H. Xu, J. Yang, Q. Yang and Z. Mao (2019). "Chaperone-mediated autophagy: Advances from bench to bedside." Neurobiol Dis 122: 41-48.
    54. Li, Z., C. Wang, Z. Wang, C. Zhu, J. Li, T. Sha, L. Ma, C. Gao, Y. Yang, Y. Sun, J. Wang, X. Sun, C. Lu, M. Difiglia, Y. Mei, C. Ding, S. Luo, Y. Dang, Y. Ding, Y. Fei and B. Lu (2019). "Allele-selective lowering of mutant HTT protein by HTT-LC3 linker compounds." Nature 575(7781): 203-209.
    55. Machida, Y., T. Okada, M. Kurosawa, F. Oyama, K. Ozawa and N. Nukina (2006). "rAAV-mediated shRNA ameliorated neuropathology in Huntington disease model mouse." Biochem Biophys Res Commun 343(1): 190-197.
    56. Marat, A. L., H. Dokainish and P. S. McPherson (2011). "DENN domain proteins: regulators of Rab GTPases." J Biol Chem 286(16): 13791-13800.
    57. Marogianni, C., D. Rikos, A. Provatas, K. Dadouli, P. Ntellas, P. Tsitsi, G. Patrinos, E. Dardiotis, G. Hadjigeorgiou and G. Xiromerisiou (2019). "The role of C9orf72 in neurodegenerative disorders: a systematic review, an updated meta-analysis, and the creation of an online database." Neurobiol Aging 84: 238 e225-238 e234.
    58. Martinez-Vicente, M., Z. Talloczy, E. Wong, G. Tang, H. Koga, S. Kaushik, R. de Vries, E. Arias, S. Harris, D. Sulzer and A. M. Cuervo (2010). "Cargo recognition failure is responsible for inefficient autophagy in Huntington's disease." Nat Neurosci 13(5): 567-576.
    59. McColgan, P. and S. J. Tabrizi (2018). "Huntington's disease: a clinical review." Eur J Neurol 25(1): 24-34.
    60. McGuire, J. R., J. Rong, S. H. Li and X. J. Li (2006). "Interaction of Huntingtin-associated protein-1 with kinesin light chain: implications in intracellular trafficking in neurons." J Biol Chem 281(6): 3552-3559.
    61. Mijaljica, D., M. Prescott and R. J. Devenish (2011). "Microautophagy in mammalian cells: revisiting a 40-year-old conundrum." Autophagy 7(7): 673-682.
    62. Milner, T. A., B. S. McEwen and E. M. Waters (2014). Chapter Seven - Estrogen Effects on Hippocampal Synapses. The Synapse. V. Pickel and M. Segal. Boston, Academic Press: 195-219.
    63. Mizushima, N. (2007). "Autophagy: process and function." Genes Dev 21(22): 2861-2873.
    64. Mizushima, N., T. Yoshimori and B. Levine (2010). "Methods in mammalian autophagy research." Cell 140(3): 313-326.
    65. Monteys, A. M., S. A. Ebanks, M. S. Keiser and B. L. Davidson (2017). "CRISPR/Cas9 Editing of the Mutant Huntingtin Allele In Vitro and In Vivo." Mol Ther 25(1): 12-23.
    66. Morfini, G. A., M. R. Burns, D. L. Stenoien and S. T. Brady (2012). Chapter 8 - Axonal Transport. Basic Neurochemistry (Eighth Edition). S. T. Brady, G. J. Siegel, R. W. Albers and D. L. Price. New York, Academic Press: 146-164.
    67. Morfini, G. A., Y. M. You, S. L. Pollema, A. Kaminska, K. Liu, K. Yoshioka, B. Bjorkblom, E. T. Coffey, C. Bagnato, D. Han, C. F. Huang, G. Banker, G. Pigino and S. T. Brady (2009). "Pathogenic huntingtin inhibits fast axonal transport by activating JNK3 and phosphorylating kinesin." Nat Neurosci 12(7): 864-871.
    68. Myers, R. H. (2004). "Huntington's disease genetics." NeuroRx 1(2): 255-262.
    69. Nedelsky, N. B., P. K. Todd and J. P. Taylor (2008). "Autophagy and the ubiquitin-proteasome system: collaborators in neuroprotection." Biochim Biophys Acta 1782(12): 691-699.
    70. Pang, W. and F. Hu (2021). "Cellular and physiological functions of C9ORF72 and implications for ALS/FTD." J Neurochem 157(3): 334-350.
    71. Pickart, C. M. and R. E. Cohen (2004). "Proteasomes and their kin: proteases in the machine age." Nat Rev Mol Cell Biol 5(3): 177-187.
    72. Reiner, A., I. Dragatsis and P. Dietrich (2011). "Genetics and neuropathology of Huntington's disease." Int Rev Neurobiol 98: 325-372.
    73. Richard, G. F., D. Viterbo, V. Khanna, V. Mosbach, L. Castelain and B. Dujon (2014). "Highly specific contractions of a single CAG/CTG trinucleotide repeat by TALEN in yeast." PLoS One 9(4): e95611.
    74. Rodrigues, F. B., D. Abreu, J. Damasio, N. Goncalves, L. Correia-Guedes, M. Coelho, J. J. Ferreira and R. I. o. t. E. H. s. D. Network (2017). "Survival, Mortality, Causes and Places of Death in a European Huntington's Disease Prospective Cohort." Mov Disord Clin Pract 4(5): 737-742.
    75. Saudou, F. and S. Humbert (2016). "The Biology of Huntingtin." Neuron 89(5): 910-926.
    76. Schneider, S. A. and T. Bird (2016). "Huntington's Disease, Huntington's Disease Look-Alikes, and Benign Hereditary Chorea: What's New?" Mov Disord Clin Pract 3(4): 342-354.
    77. Sellier, C., M. L. Campanari, C. Julie Corbier, A. Gaucherot, I. Kolb-Cheynel, M. Oulad-Abdelghani, F. Ruffenach, A. Page, S. Ciura, E. Kabashi and N. Charlet-Berguerand (2016). "Loss of C9ORF72 impairs autophagy and synergizes with polyQ Ataxin-2 to induce motor neuron dysfunction and cell death." EMBO J 35(12): 1276-1297.
    78. Shin, J. W., K. H. Kim, M. J. Chao, R. S. Atwal, T. Gillis, M. E. MacDonald, J. F. Gusella and J. M. Lee (2016). "Permanent inactivation of Huntington's disease mutation by personalized allele-specific CRISPR/Cas9." Hum Mol Genet 25(20): 4566-4576.
    79. Sleigh, J. N., A. M. Rossor, A. D. Fellows, A. P. Tosolini and G. Schiavo (2019). "Axonal transport and neurological disease." Nat Rev Neurol 15(12): 691-703.
    80. Soares, T. R., S. D. Reis, B. R. Pinho, M. R. Duchen and J. M. A. Oliveira (2019). "Targeting the proteostasis network in Huntington's disease." Ageing Res Rev 49: 92-103.
    81. Solberg, O. K., P. Filkukova, J. C. Frich and K. J. B. Feragen (2018). "Age at Death and Causes of Death in Patients with Huntington Disease in Norway in 1986-2015." J Huntingtons Dis 7(1): 77-86.
    82. Stahl, C. M. and A. Feigin (2020). "Medical, Surgical, and Genetic Treatment of Huntington Disease." Neurol Clin 38(2): 367-378.
    83. Stanek, L. M., S. P. Sardi, B. Mastis, A. R. Richards, C. M. Treleaven, T. Taksir, K. Misra, S. H. Cheng and L. S. Shihabuddin (2014). "Silencing mutant huntingtin by adeno-associated virus-mediated RNA interference ameliorates disease manifestations in the YAC128 mouse model of Huntington's disease." Hum Gene Ther 25(5): 461-474.
    84. Stanek, L. M., W. Yang, S. Angus, P. S. Sardi, M. R. Hayden, G. H. Hung, C. F. Bennett, S. H. Cheng and L. S. Shihabuddin (2013). "Antisense oligonucleotide-mediated correction of transcriptional dysregulation is correlated with behavioral benefits in the YAC128 mouse model of Huntington's disease." J Huntingtons Dis 2(2): 217-228.
    85. Sullivan, P. M., X. Zhou, A. M. Robins, D. H. Paushter, D. Kim, M. B. Smolka and F. Hu (2016). "The ALS/FTLD associated protein C9orf72 associates with SMCR8 and WDR41 to regulate the autophagy-lysosome pathway." Acta Neuropathol Commun 4(1): 51.
    86. Sun, X., H. Gao, Y. Yang, M. He, Y. Wu, Y. Song, Y. Tong and Y. Rao (2019). "PROTACs: great opportunities for academia and industry." Signal Transduct Target Ther 4: 64.
    87. Tabrizi, S. J., B. R. Leavitt, G. B. Landwehrmeyer, E. J. Wild, C. Saft, R. A. Barker, N. F. Blair, D. Craufurd, J. Priller, H. Rickards, A. Rosser, H. B. Kordasiewicz, C. Czech, E. E. Swayze, D. A. Norris, T. Baumann, I. Gerlach, S. A. Schobel, E. Paz, A. V. Smith, C. F. Bennett, R. M. Lane and I.-H. S. S. T. Phase 1-2a (2019). "Targeting Huntingtin Expression in Patients with Huntington's Disease." N Engl J Med 380(24): 2307-2316.
    88. Tang, B. L. (2016). "C9orf72's Interaction with Rab GTPases-Modulation of Membrane Traffic and Autophagy." Front Cell Neurosci 10: 228.
    89. Tartari, M., C. Gissi, V. Lo Sardo, C. Zuccato, E. Picardi, G. Pesole and E. Cattaneo (2008). "Phylogenetic comparison of huntingtin homologues reveals the appearance of a primitive polyQ in sea urchin." Mol Biol Evol 25(2): 330-338.
    90. Thrower, J. S., L. Hoffman, M. Rechsteiner and C. M. Pickart (2000). "Recognition of the polyubiquitin proteolytic signal." EMBO J 19(1): 94-102.
    91. Trushina, E., R. B. Dyer, J. D. Badger, 2nd, D. Ure, L. Eide, D. D. Tran, B. T. Vrieze, V. Legendre-Guillemin, P. S. McPherson, B. S. Mandavilli, B. Van Houten, S. Zeitlin, M. McNiven, R. Aebersold, M. Hayden, J. E. Parisi, E. Seeberg, I. Dragatsis, K. Doyle, A. Bender, C. Chacko and C. T. McMurray (2004). "Mutant huntingtin impairs axonal trafficking in mammalian neurons in vivo and in vitro." Mol Cell Biol 24(18): 8195-8209.
    92. Varshavsky, A. (1997). "The ubiquitin system." Trends Biochem Sci 22(10): 383-387.
    93. Vonsattel, J. P. and M. DiFiglia (1998). "Huntington disease." J Neuropathol Exp Neurol 57(5): 369-384.
    94. Waelter, S., A. Boeddrich, R. Lurz, E. Scherzinger, G. Lueder, H. Lehrach and E. E. Wanker (2001). "Accumulation of mutant huntingtin fragments in aggresome-like inclusion bodies as a result of insufficient protein degradation." Mol Biol Cell 12(5): 1393-1407.
    95. Wang, J., C. E. Wang, A. Orr, S. Tydlacka, S. H. Li and X. J. Li (2008). "Impaired ubiquitin-proteasome system activity in the synapses of Huntington's disease mice." J Cell Biol 180(6): 1177-1189.
    96. Wang, M., H. Wang, Z. Tao, Q. Xia, Z. Hao, J. H. M. Prehn, X. Zhen, G. Wang and Z. Ying (2020). "C9orf72 associates with inactive Rag GTPases and regulates mTORC1-mediated autophagosomal and lysosomal biogenesis." Aging Cell 19(4): e13126.
    97. Webster, C. P., E. F. Smith, C. S. Bauer, A. Moller, G. M. Hautbergue, L. Ferraiuolo, M. A. Myszczynska, A. Higginbottom, M. J. Walsh, A. J. Whitworth, B. K. Kaspar, K. Meyer, P. J. Shaw, A. J. Grierson and K. J. De Vos (2016). "The C9orf72 protein interacts with Rab1a and the ULK1 complex to regulate initiation of autophagy." EMBO J 35(15): 1656-1676.
    98. Wong, E. and A. M. Cuervo (2010). "Autophagy gone awry in neurodegenerative diseases." Nat Neurosci 13(7): 805-811.
    99. Wong, Y. C. and E. L. Holzbaur (2014). "The regulation of autophagosome dynamics by huntingtin and HAP1 is disrupted by expression of mutant huntingtin, leading to defective cargo degradation." J Neurosci 34(4): 1293-1305.
    100. Xiao, S., L. MacNair, P. McGoldrick, P. M. McKeever, J. R. McLean, M. Zhang, J. Keith, L. Zinman, E. Rogaeva and J. Robertson (2015). "Isoform-specific antibodies reveal distinct subcellular localizations of C9orf72 in amyotrophic lateral sclerosis." Ann Neurol 78(4): 568-583.
    101. Xiao, S., P. M. McKeever, A. Lau and J. Robertson (2019). "Synaptic localization of C9orf72 regulates post-synaptic glutamate receptor 1 levels." Acta Neuropathol Commun 7(1): 161.
    102. Yang, S., R. Chang, H. Yang, T. Zhao, Y. Hong, H. E. Kong, X. Sun, Z. Qin, P. Jin, S. Li and X. J. Li (2017). "CRISPR/Cas9-mediated gene editing ameliorates neurotoxicity in mouse model of Huntington's disease." J Clin Invest 127(7): 2719-2724.
    103. Yang, Z. and D. J. Klionsky (2010). "Mammalian autophagy: core molecular machinery and signaling regulation." Curr Opin Cell Biol 22(2): 124-131.
    104. Zeitler, B., S. Froelich, K. Marlen, D. A. Shivak, Q. Yu, D. Li, J. R. Pearl, J. C. Miller, L. Zhang, D. E. Paschon, S. J. Hinkley, I. Ankoudinova, S. Lam, D. Guschin, L. Kopan, J. M. Cherone, H. B. Nguyen, G. Qiao, Y. Ataei, M. C. Mendel, R. Amora, R. Surosky, J. Laganiere, B. J. Vu, A. Narayanan, Y. Sedaghat, K. Tillack, C. Thiede, A. Gartner, S. Kwak, J. Bard, L. Mrzljak, L. Park, T. Heikkinen, K. K. Lehtimaki, M. M. Svedberg, J. Haggkvist, L. Tari, M. Toth, A. Varrone, C. Halldin, A. E. Kudwa, S. Ramboz, M. Day, J. Kondapalli, D. J. Surmeier, F. D. Urnov, P. D. Gregory, E. J. Rebar, I. Munoz-Sanjuan and H. S. Zhang (2019). "Allele-selective transcriptional repression of mutant HTT for the treatment of Huntington's disease." Nat Med 25(7): 1131-1142.
    105. Zhang, K. Y., S. Yang, S. T. Warraich and I. P. Blair (2014). "Ubiquilin 2: a component of the ubiquitin-proteasome system with an emerging role in neurodegeneration." Int J Biochem Cell Biol 50: 123-126.
    106. Zhu, J. W., Y. F. Li, Z. T. Wang, W. Q. Jia and R. X. Xu (2016). "Toll-Like Receptor 4 Deficiency Impairs Motor Coordination." Front Neurosci 10: 33.
    107. Zuccato, C., M. Valenza and E. Cattaneo (2010). "Molecular mechanisms and potential therapeutical targets in Huntington's disease." Physiol Rev 90(3): 905-981.

    下載圖示
    2026-07-14公開
    QR CODE