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| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 楊家榮(Chia-Ron Yang) | |
| dc.contributor.author | Yu-Ting Yu | en |
| dc.contributor.author | 游育婷 | zh_TW |
| dc.date.accessioned | 2021-07-11T15:04:27Z | - |
| dc.date.available | 2024-10-09 | |
| dc.date.copyright | 2019-10-09 | |
| dc.date.issued | 2019 | |
| dc.date.submitted | 2019-08-15 | |
| dc.identifier.citation | 1 Dehay, B., Bourdenx, M., Gorry, P., Przedborski, S., Vila, M., Hunot, S. et al. Targeting α-synuclein for treatment of Parkinson's disease: mechanistic and therapeutic considerations. The Lancet. Neurology (2015) 14, 855-866.
2 Lashuel, H. A., Overk, C. R., Oueslati, A. & Masliah, E. The many faces of alpha-synuclein: from structure and toxicity to therapeutic target. Nature reviews. Neuroscience (2013) 14, 38-48. 3 Global, regional, and national burden of Parkinson's disease, 1990-2016: a systematic analysis for the Global Burden of Disease Study 2016. The Lancet. Neurology (2018) 17, 939-953. 4 George, S. & Brundin, P. Immunotherapy in Parkinson's Disease: Micromanaging Alpha-Synuclein Aggregation. Journal of Parkinson's disease (2015) 5, 413-424. 5 Muller, C. M., de Vos, R. A., Maurage, C. A., Thal, D. R., Tolnay, M. & Braak, H. Staging of sporadic Parkinson disease-related alpha-synuclein pathology: inter- and intra-rater reliability. Journal of neuropathology and experimental neurology (2005) 64, 623-628. 6 Dickson, D. W. Parkinson's disease and parkinsonism: neuropathology. Cold Spring Harbor perspectives in medicine (2012) 2, 8. 7 Fox, S. H., Katzenschlager, R., Lim, S. Y., Barton, B., de Bie, R. M. A., Seppi, K. et al. International Parkinson and movement disorder society evidence-based medicine review: Update on treatments for the motor symptoms of Parkinson's disease. Movement disorders (2018) 33, 1248-1266. 8 Ives, N. J., Stowe, R. L., Marro, J., Counsell, C., Macleod, A., Clarke, C. E. et al. Monoamine oxidase type B inhibitors in early Parkinson's disease: meta-analysis of 17 randomised trials involving 3525 patients. BMJ (2004) 329, 593. 9 Bressman, S. & Saunders-Pullman, R. When to Start Levodopa Therapy for Parkinson's Disease. The New England journal of medicine (2019) 380, 389-390. 10 Hansen, C., Angot, E., Bergstrom, A. L., Steiner, J. A., Pieri, L., Paul, G. et al. alpha-Synuclein propagates from mouse brain to grafted dopaminergic neurons and seeds aggregation in cultured human cells. The Journal of clinical investigation (2011) 121, 715-725. 11 Ono, K. The Oligomer Hypothesis in alpha-Synucleinopathy. Neurochemical research (2017) 42, 3362-3371. 12 Bellucci, A., Zaltieri, M., Navarria, L., Grigoletto, J., Missale, C. & Spano, P. From alpha-synuclein to synaptic dysfunctions: new insights into the pathophysiology of Parkinson's disease. Brain research (2012) 1476, 183-202. 13 Rao, J. N., Dua, V. & Ulmer, T. S. Characterization of alpha-synuclein interactions with selected aggregation-inhibiting small molecules. Biochemistry (2008) 47, 4651-4656. 14 Wrasidlo, W., Tsigelny, I. F., Price, D. L., Dutta, G., Rockenstein, E., Schwarz, T. C. et al. A de novo compound targeting alpha-synuclein improves deficits in models of Parkinson's disease. Brain (2016) 139, 3217-3236. 15 Ueda, K., Fukushima, H., Masliah, E., Xia, Y., Iwai, A., Yoshimoto, M. et al. Molecular cloning of cDNA encoding an unrecognized component of amyloid in Alzheimer disease. Proceedings of the National Academy of Sciences of the United States of America (1993) 90, 11282-11286. 16 Han, H., Weinreb, P. H. & Lansbury, P. T., Jr. The core Alzheimer's peptide NAC forms amyloid fibrils which seed and are seeded by beta-amyloid: is NAC a common trigger or target in neurodegenerative disease? Chemistry & biology (1995) 2, 163-169. 17 Emanuele, M. & Chieregatti, E. Mechanisms of alpha-synuclein action on neurotransmission: cell-autonomous and non-cell autonomous role. Biomolecules (2015) 5, 865-892. 18 Burre, J. The Synaptic Function of alpha-Synuclein. Journal of Parkinson's disease (2015) 5, 699-713. 19 Bendor, J. T., Logan, T. P. & Edwards, R. H. The function of alpha-synuclein. Neuron (2013) 79, 1044-1066. 20 Burre, J., Sharma, M. & Sudhof, T. C. Definition of a molecular pathway mediating alpha-synuclein neurotoxicity. The Journal of neuroscience (2015) 35, 5221-5232. 21 Conway, K. A., Lee, S. J., Rochet, J. C., Ding, T. T., Williamson, R. E. & Lansbury, P. T., Jr. Acceleration of oligomerization, not fibrillization, is a shared property of both alpha-synuclein mutations linked to early-onset Parkinson's disease: implications for pathogenesis and therapy. Proceedings of the National Academy of Sciences of the United States of America (2000) 97, 571-576. 22 Winner, B., Jappelli, R., Maji, S. K., Desplats, P. A., Boyer, L., Aigner, S. et al. In vivo demonstration that alpha-synuclein oligomers are toxic. Proceedings of the National Academy of Sciences of the United States of America (2011) 108, 4194-4199. 23 Sharon, R., Bar-Joseph, I., Frosch, M. P., Walsh, D. M., Hamilton, J. A. & Selkoe, D. J. The formation of highly soluble oligomers of alpha-synuclein is regulated by fatty acids and enhanced in Parkinson's disease. Neuron (2003) 37, 583-595. 24 Peelaerts, W., Bousset, L., Van der Perren, A., Moskalyuk, A., Pulizzi, R., Giugliano, M. et al. alpha-Synuclein strains cause distinct synucleinopathies after local and systemic administration. Nature (2015) 522, 340-344. 25 Pieri, L., Madiona, K., Bousset, L. & Melki, R. Fibrillar α-synuclein and huntingtin exon 1 assemblies are toxic to the cells. Biophysical journal (2012) 102, 2894-2905. 26 Kahle, P. J., Neumann, M., Ozmen, L., Muller, V., Jacobsen, H., Schindzielorz, A. et al. Subcellular localization of wild-type and Parkinson's disease-associated mutant alpha -synuclein in human and transgenic mouse brain. The Journal of neuroscience (2000) 20, 6365-6373. 27 Davidson, W. S., Jonas, A., Clayton, D. F. & George, J. M. Stabilization of alpha-synuclein secondary structure upon binding to synthetic membranes. Journal of Biological Chemistry (1998) 273, 9443-9449. 28 Varkey, J., Isas, J. M., Mizuno, N., Jensen, M. B., Bhatia, V. K., Jao, C. C. et al. Membrane curvature induction and tubulation are common features of synucleins and apolipoproteins. Journal of Biological Chemistry (2010) 285, 32486-32493. 29 Nunnari, J. & Suomalainen, A. Mitochondria: in sickness and in health. Cell (2012) 148, 1145-1159. 30 Bengoa-Vergniory, N., Roberts, R. F., Wade-Martins, R. & Alegre-Abarrategui, J. Alpha-synuclein oligomers: a new hope. Acta neuropathologica (2017) 134, 819-838. 31 Wong, Y. C. & Krainc, D. alpha-synuclein toxicity in neurodegeneration: mechanism and therapeutic strategies. Nature medicine (2017) 23, 1-13. 32 Luth, E. S., Stavrovskaya, I. G., Bartels, T., Kristal, B. S. & Selkoe, D. J. Soluble, prefibrillar alpha-synuclein oligomers promote complex I-dependent, Ca2+-induced mitochondrial dysfunction. Journal of Biological Chemistry (2014) 289, 21490-21507. 33 Outeiro, T. F. & Lindquist, S. Yeast cells provide insight into alpha-synuclein biology and pathobiology. Science (2003) 302, 1772-1775. 34 Caraveo, G., Auluck, P. K., Whitesell, L., Chung, C. Y., Baru, V., Mosharov, E. V. et al. Calcineurin determines toxic versus beneficial responses to alpha-synuclein. Proceedings of the National Academy of Sciences of the United States of America (2014) 111, 3544-3552. 35 Colla, E., Jensen, P. H., Pletnikova, O., Troncoso, J. C., Glabe, C. & Lee, M. K. Accumulation of toxic alpha-synuclein oligomer within endoplasmic reticulum occurs in alpha-synucleinopathy in vivo. The Journal of neuroscience (2012) 32, 3301-3305. 36 Wong, Y. C. & Holzbaur, E. L. Autophagosome dynamics in neurodegeneration at a glance. Journal of cell science (2015) 128, 1259-1267. 37 Tanik, S. A., Schultheiss, C. E., Volpicelli-Daley, L. A., Brunden, K. R. & Lee, V. M. Lewy body-like alpha-synuclein aggregates resist degradation and impair macroautophagy. Journal of Biological Chemistry (2013) 288, 15194-15210. 38 Mazzulli, J. R., Xu, Y. H., Sun, Y., Knight, A. L., McLean, P. J., Caldwell, G. A. et al. Gaucher disease glucocerebrosidase and alpha-synuclein form a bidirectional pathogenic loop in synucleinopathies. Cell (2011) 146, 37-52. 39 Mazzulli, J. R., Zunke, F., Isacson, O., Studer, L. & Krainc, D. alpha-Synuclein-induced lysosomal dysfunction occurs through disruptions in protein trafficking in human midbrain synucleinopathy models. Proceedings of the National Academy of Sciences of the United States of America (2016) 113, 1931-1936. 40 Recasens, A., Dehay, B., Bove, J., Carballo-Carbajal, I., Dovero, S., Perez-Villalba, A. et al. Lewy body extracts from Parkinson disease brains trigger alpha-synuclein pathology and neurodegeneration in mice and monkeys. Annals of neurology (2014) 75, 351-362. 41 Li, J. Y., Englund, E., Holton, J. L., Soulet, D., Hagell, P., Lees, A. J. et al. Lewy bodies in grafted neurons in subjects with Parkinson's disease suggest host-to-graft disease propagation. Nature medicine (2008) 14, 501-503. 42 Gallegos, S., Pacheco, C., Peters, C., Opazo, C. M. & Aguayo, L. G. Features of alpha-synuclein that could explain the progression and irreversibility of Parkinson's disease. Frontiers in neuroscience (2015) 9, 59. 43 Luk, K. C., Song, C., O'Brien, P., Stieber, A., Branch, J. R., Brunden, K. R. et al. Exogenous alpha-synuclein fibrils seed the formation of Lewy body-like intracellular inclusions in cultured cells. Proceedings of the National Academy of Sciences of the United States of America (2009) 106, 20051-20056. 44 Luk, K. C., Kehm, V., Carroll, J., Zhang, B., O'Brien, P., Trojanowski, J. Q. et al. Pathological alpha-synuclein transmission initiates Parkinson-like neurodegeneration in nontransgenic mice. Science (2012) 338, 949-953. 45 Danzer, K. M., Kranich, L. R., Ruf, W. P., Cagsal-Getkin, O., Winslow, A. R., Zhu, L. et al. Exosomal cell-to-cell transmission of alpha synuclein oligomers. Molecular neurodegeneration (2012) 7, 42. 46 Tang, Y. & Le, W. Differential Roles of M1 and M2 Microglia in Neurodegenerative Diseases. Molecular neurobiology (2016) 53, 1181-1194. 47 Subramaniam, S. R. & Federoff, H. J. Targeting Microglial Activation States as a Therapeutic Avenue in Parkinson's Disease. Frontiers in aging neuroscience (2017) 9, 176. 48 Mosher, K. I. & Wyss-Coray, T. Microglial dysfunction in brain aging and Alzheimer's disease. Biochemical pharmacology (2014) 88, 594-604. 49 Popiolek-Barczyk, K. & Mika, J. Targeting the Microglial Signaling Pathways: New Insights in the Modulation of Neuropathic Pain. Current medicinal chemistry (2016) 23, 2908-2928. 50 Zella, M. A. S., Metzdorf, J., Ostendorf, F., Maass, F., Muhlack, S., Gold, R. et al. Novel Immunotherapeutic Approaches to Target Alpha-Synuclein and Related Neuroinflammation in Parkinson's Disease. Cells (2019) 8, 105. 51 Masliah, E., Rockenstein, E., Adame, A., Alford, M., Crews, L., Hashimoto, M. et al. Effects of alpha-synuclein immunization in a mouse model of Parkinson's disease. Neuron (2005) 46, 857-868. 52 Masliah, E., Rockenstein, E., Mante, M., Crews, L., Spencer, B., Adame, A. et al. Passive immunization reduces behavioral and neuropathological deficits in an alpha-synuclein transgenic model of Lewy body disease. PloS one (2011) 6, 19338. 53 Games, D., Valera, E., Spencer, B., Rockenstein, E., Mante, M., Adame, A. et al. Reducing C-terminal-truncated alpha-synuclein by immunotherapy attenuates neurodegeneration and propagation in Parkinson's disease-like models. The Journal of neuroscience (2014) 34, 9441-9454. 54 Tran, H. T., Chung, C. H., Iba, M., Zhang, B., Trojanowski, J. Q., Luk, K. C. et al. Α-synuclein immunotherapy blocks uptake and templated propagation of misfolded α-synuclein and neurodegeneration. Cell reports (2014) 7, 2054-2065. 55 Saunders-Pullman, R., Mirelman, A., Alcalay, R. N., Wang, C., Ortega, R. A., Raymond, D. et al. Progression in the LRRK2-Asssociated Parkinson Disease Population. JAMA neurology (2018) 75, 312-319. 56 Mazzulli, J. R., Zunke, F., Tsunemi, T., Toker, N. J., Jeon, S., Burbulla, L. F. et al. Activation of beta-Glucocerebrosidase Reduces Pathological alpha-Synuclein and Restores Lysosomal Function in Parkinson's Patient Midbrain Neurons. The Journal of neuroscience (2016) 36, 7693-7706. 57 Migdalska-Richards, A., Daly, L., Bezard, E. & Schapira, A. H. Ambroxol effects in glucocerebrosidase and alpha-synuclein transgenic mice. Annals of neurology (2016) 80, 766-775. 58 West, A. B. Achieving neuroprotection with LRRK2 kinase inhibitors in Parkinson disease. Experimental neurology (2017) 298, 236-245. 59 Gorbatyuk, O. S., Li, S., Nash, K., Gorbatyuk, M., Lewin, A. S., Sullivan, L. F. et al. In vivo RNAi-mediated alpha-synuclein silencing induces nigrostriatal degeneration. Molecular therapy (2010) 18, 1450-1457. 60 Khodr, C. E., Becerra, A., Han, Y. & Bohn, M. C. Targeting alpha-synuclein with a microRNA-embedded silencing vector in the rat substantia nigra: positive and negative effects. Brain research (2014) 1550, 47-60. 61 Bieschke, J., Russ, J., Friedrich, R. P., Ehrnhoefer, D. E., Wobst, H., Neugebauer, K. et al. EGCG remodels mature alpha-synuclein and amyloid-beta fibrils and reduces cellular toxicity. Proceedings of the National Academy of Sciences of the United States of America (2010) 107, 7710-7715. 62 Wagner, J., Ryazanov, S., Leonov, A., Levin, J., Shi, S., Schmidt, F. et al. Anle138b: a novel oligomer modulator for disease-modifying therapy of neurodegenerative diseases such as prion and Parkinson's disease. Acta neuropathologica (2013) 125, 795-813. 63 Prabhudesai, S., Sinha, S., Attar, A., Kotagiri, A., Fitzmaurice, A. G., Lakshmanan, R. et al. A novel 'molecular tweezer' inhibitor of alpha-synuclein neurotoxicity in vitro and in vivo. Neurotherapeutics (2012) 9, 464-476. 64 Price, D. L., Koike, M. A., Khan, A., Wrasidlo, W., Rockenstein, E., Masliah, E. et al. The small molecule alpha-synuclein misfolding inhibitor, NPT200-11, produces multiple benefits in an animal model of Parkinson's disease. Scientific reports (2018) 8, 16165. 65 Xilouri, M., Vogiatzi, T., Vekrellis, K., Park, D. & Stefanis, L. Abberant alpha-synuclein confers toxicity to neurons in part through inhibition of chaperone-mediated autophagy. PloS one (2009) 4, 5515. 66 Decressac, M., Mattsson, B., Weikop, P., Lundblad, M., Jakobsson, J. & Bjorklund, A. TFEB-mediated autophagy rescues midbrain dopamine neurons from alpha-synuclein toxicity. Proceedings of the National Academy of Sciences of the United States of America (2013) 110, 1817-1826. 67 Lee, S., Kim, S., Park, Y. J., Yun, S. P., Kwon, S. H., Kim, D. et al. The c-Abl inhibitor, Radotinib HCl, is neuroprotective in a preclinical Parkinson's disease mouse model. Human molecular genetics (2018) 27, 2344-2356. 68 Spencer, B., Potkar, R., Trejo, M., Rockenstein, E., Patrick, C., Gindi, R. et al. Beclin 1 gene transfer activates autophagy and ameliorates the neurodegenerative pathology in alpha-synuclein models of Parkinson's and Lewy body diseases. The Journal of neuroscience (2009) 29, 13578-13588. 69 Cuervo, A. M., Stefanis, L., Fredenburg, R., Lansbury, P. T. & Sulzer, D. Impaired degradation of mutant alpha-synuclein by chaperone-mediated autophagy. Science (2004) 305, 1292-1295. 70 Schneeberger, A., Tierney, L. & Mandler, M. Active immunization therapies for Parkinson's disease and multiple system atrophy. Movement disorders (2016) 31, 214-224. 71 Rockenstein, E., Mallory, M., Hashimoto, M., Song, D., Shults, C. W., Lang, I. et al. Differential neuropathological alterations in transgenic mice expressing alpha-synuclein from the platelet-derived growth factor and Thy-1 promoters. Journal of neuroscience research (2002) 68, 568-578. 72 Sanchez-Guajardo, V., Annibali, A., Jensen, P. H. & Romero-Ramos, M. alpha-Synuclein vaccination prevents the accumulation of parkinson disease-like pathologic inclusions in striatum in association with regulatory T cell recruitment in a rat model. Journal of neuropathology and experimental neurology (2013) 72, 624-645. 73 Mandler, M., Valera, E., Rockenstein, E., Weninger, H., Patrick, C., Adame, A. et al. Next-generation active immunization approach for synucleinopathies: implications for Parkinson's disease clinical trials. Acta neuropathologica (2014) 127, 861-879. 74 Valera, E. & Masliah, E. Immunotherapy for neurodegenerative diseases: focus on alpha-synucleinopathies. Pharmacology & therapeutics (2013) 138, 311-322. 75 Bergstrom, A. L., Kallunki, P. & Fog, K. Development of Passive Immunotherapies for Synucleinopathies. Movement disorders (2016) 31, 203-213. 76 Spencer, B., Emadi, S., Desplats, P., Eleuteri, S., Michael, S., Kosberg, K. et al. ESCRT-mediated uptake and degradation of brain-targeted α-synuclein single chain antibody attenuates neuronal degeneration in vivo. Molecular therapy (2014) 22, 1753-1767. 77 Bae, E. J., Lee, H. J., Rockenstein, E., Ho, D. H., Park, E. B., Yang, N. Y. et al. Antibody-aided clearance of extracellular alpha-synuclein prevents cell-to-cell aggregate transmission. The Journal of neuroscience (2012) 32, 13454-13469. 78 Lorenzen, N., Lemminger, L., Pedersen, J. N., Nielsen, S. B. & Otzen, D. E. The N-terminus of alpha-synuclein is essential for both monomeric and oligomeric interactions with membranes. FEBS letters (2014) 588, 497-502. 79 Shahaduzzaman, M., Nash, K., Hudson, C., Sharif, M., Grimmig, B., Lin, X. et al. Anti-human α-synuclein N-terminal peptide antibody protects against dopaminergic cell death and ameliorates behavioral deficits in an AAV-α-synuclein rat model of Parkinson's disease. PloS one (2015) 10, e0116841. 80 Nasstrom, T., Goncalves, S., Sahlin, C., Nordstrom, E., Screpanti Sundquist, V., Lannfelt, L. et al. Antibodies against alpha-synuclein reduce oligomerization in living cells. PloS one (2011) 6, 27230. 81 Pacheco, C. R., Morales, C. N., Ramirez, A. E., Munoz, F. J., Gallegos, S. S., Caviedes, P. A. et al. Extracellular alpha-synuclein alters synaptic transmission in brain neurons by perforating the neuronal plasma membrane. Journal of neurochemistry (2015) 132, 731-741. 82 Mao, X., Ou, M. T., Karuppagounder, S. S., Kam, T. I., Yin, X., Xiong, Y. et al. Pathological alpha-synuclein transmission initiated by binding lymphocyte-activation gene 3. Science (2016) 353. 83 Sardi, S. P., Cedarbaum, J. M. & Brundin, P. Targeted Therapies for Parkinson's Disease: From Genetics to the Clinic. Movement disorders (2018) 33, 684-696. 84 Levenson, J. M., Schroeter, S., Carroll, J. C., Cullen, V., Asp, E., Proschitsky, M. et al. NPT088 reduces both amyloid-beta and tau pathologies in transgenic mice. Alzheimer's & dementia (2016) 2, 141-155. 85 Brahmachari, S., Karuppagounder, S. S., Ge, P., Lee, S., Dawson, V. L., Dawson, T. M. et al. c-Abl and Parkinson's Disease: Mechanisms and Therapeutic Potential. Journal of Parkinson's disease (2017) 7, 589-601. 86 Schenk, D. B., Koller, M., Ness, D. K., Griffith, S. G., Grundman, M., Zago, W. et al. First-in-human assessment of PRX002, an anti-alpha-synuclein monoclonal antibody, in healthy volunteers. Movement disorders (2017) 32, 211-218. 87 Weihofen, A., Liu, Y., Arndt, J. W., Huy, C., Quan, C., Smith, B. A. et al. Development of an aggregate-selective, human-derived alpha-synuclein antibody BIIB054 that ameliorates disease phenotypes in Parkinson's disease models. Neurobiology of disease (2019) 124, 276-288. 88 Sardi, S. P., Viel, C., Clarke, J., Treleaven, C. M., Richards, A. M., Park, H. et al. Glucosylceramide synthase inhibition alleviates aberrations in synucleinopathy models. Proceedings of the National Academy of Sciences of the United States of America (2017) 114, 2699-2704. 89 Huang, L., Su, X. & Federoff, H. J. Single-chain fragment variable passive immunotherapies for neurodegenerative diseases. International journal of molecular sciences (2013) 14, 19109-19127. 90 Valera, E., Spencer, B. & Masliah, E. Immunotherapeutic Approaches Targeting Amyloid-beta, alpha-Synuclein, and Tau for the Treatment of Neurodegenerative Disorders. Neurotherapeutics (2016) 13, 179-189. 91 Zhou, C., Emadi, S., Sierks, M. R. & Messer, A. A human single-chain Fv intrabody blocks aberrant cellular effects of overexpressed alpha-synuclein. Molecular therapy (2004) 10, 1023-1031. 92 Wang, Y. J., Pollard, A., Zhong, J. H., Dong, X. Y., Wu, X. B., Zhou, H. D. et al. Intramuscular delivery of a single chain antibody gene reduces brain Abeta burden in a mouse model of Alzheimer's disease. Neurobiology of aging (2009) 30, 364-376. 93 Emadi, S., Barkhordarian, H., Wang, M. S., Schulz, P. & Sierks, M. R. Isolation of a human single chain antibody fragment against oligomeric alpha-synuclein that inhibits aggregation and prevents alpha-synuclein-induced toxicity. Journal of molecular biology (2007) 368, 1132-1144. 94 Emadi, S., Kasturirangan, S., Wang, M. S., Schulz, P. & Sierks, M. R. Detecting morphologically distinct oligomeric forms of alpha-synuclein. Journal of Biological Chemistry (2009) 284, 11048-11058. 95 Singer, T. P. & Ramsay, R. R. Mechanism of the neurotoxicity of MPTP. An update. FEBS letters (1990) 274, 1-8. 96 Wang, S., He, H., Chen, L., Zhang, W., Zhang, X. & Chen, J. Protective effects of salidroside in the MPTP/MPP(+)-induced model of Parkinson's disease through ROS-NO-related mitochondrion pathway. Molecular neurobiology (2015) 51, 718-728. 97 Li, X., Ye, X., Li, X., Sun, X., Liang, Q., Tao, L. et al. Salidroside protects against MPP(+)-induced apoptosis in PC12 cells by inhibiting the NO pathway. Brain research (2011) 1382, 9-18. 98 Kowall, N. W., Hantraye, P., Brouillet, E., Beal, M. F., McKee, A. C. & Ferrante, R. J. MPTP induces alpha-synuclein aggregation in the substantia nigra of baboons. Neuroreport (2000) 11, 211-213. 99 Eliezer, D., Kutluay, E., Bussell, R., Jr. & Browne, G. Conformational properties of alpha-synuclein in its free and lipid-associated states. Journal of molecular biology (2001) 307, 1061-1073. 100 Werle, M., Loretz, B., Entstrasser, D. & Foger, F. Design and evaluation of a chitosan-aprotinin conjugate for the peroral delivery of therapeutic peptides and proteins susceptible to enzymatic degradation. Journal of drug targeting (2007) 15, 327-333. 101 Banks, W. A., Terrell, B., Farr, S. A., Robinson, S. M., Nonaka, N. & Morley, J. E. Passage of amyloid beta protein antibody across the blood-brain barrier in a mouse model of Alzheimer's disease. Peptides (2002) 23, 2223-2226. 102 Salameh, T. S. & Banks, W. A. Delivery of therapeutic peptides and proteins to the CNS. Advances in pharmacology (San Diego, Calif.) (2014) 71, 277-299. 103 Erdlenbruch, B., Alipour, M., Fricker, G., Miller, D. S., Kugler, W., Eibl, H. et al. Alkylglycerol opening of the blood-brain barrier to small and large fluorescence markers in normal and C6 glioma-bearing rats and isolated rat brain capillaries. British journal of pharmacology (2003) 140, 1201-1210. 104 Friden, P. M., Walus, L. R., Musso, G. F., Taylor, M. A., Malfroy, B. & Starzyk, R. M. Anti-transferrin receptor antibody and antibody-drug conjugates cross the blood-brain barrier. Proceedings of the National Academy of Sciences of the United States of America (1991) 88, 4771-4775. 105 Niewoehner, J., Bohrmann, B., Collin, L., Urich, E., Sade, H., Maier, P. et al. Increased brain penetration and potency of a therapeutic antibody using a monovalent molecular shuttle. Neuron (2014) 81, 49-60. | |
| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/78567 | - |
| dc.description.abstract | 帕金森氏症是目前世界上最常見的運動障礙疾病，也是第二普遍的神經退化性疾病。患有此症的病患會有許多症狀像是不隨意顫抖、平衡困難以及無法隨意走動與移動。其中一個導致此疾病發生的病理機制為路易氏體(Lewy bodies)的不正常斑塊沉積於大腦的黑核區域。而這些不正常堆積物及是α-突觸核蛋白。α-突觸核是分子量約14至20千道耳頓的蛋白，當大量堆積在腦部時，會造成神經細胞的退化以及死亡。目前有許多對於α-突觸核蛋白於帕金森氏症上病理機轉的研究。在神經細胞中，α-突觸核蛋白會造成粒線體的功能異常、內質網的壓力上升、自噬細胞及溶小體功能異常以及突觸功能異常等等。而α-突觸核蛋白的二聚體及多聚體等會在腦中慢慢形成有毒性的纖維性α-突觸核，而這些聚集物對神經細胞皆會造成毒性與氧化壓力的上升。
本研究使用萊亨雞針對α-突觸核蛋白利用噬菌體展現技術開發了單鍊抗體(single-chain variable fragments)用來標的α-突觸核單體以及多聚體。從研究結果可以看到我們開發的單鍊抗體對於α-突觸核單體以及多聚體皆具有很高的親和性，且在試管實驗ThT aggregation assay中顯著抑制了α-突觸核蛋白的聚集。除此之外，在BiFC assay中，α-突觸核單鍊抗體也減少了α-突觸核在SH-SY5Y神經細胞中的聚集作用；在MPP+誘導α-突觸核蛋白聚集的細胞實驗模式中，α-突觸核單鍊抗體也達到相同的抑制效果，減少了單體、二聚體、三聚體及多聚體在SH-SY5Y神經細胞的表現量。此外，α-突觸核單鍊抗體在經緯靜脈注射到小鼠後，小鼠腦內的抗體量隨時間增加而增加，證實了我們開發的α-突觸核單鍊抗體具有穿透血腦障蔽的能力。 總體來說，我們開發的高親和性α-突觸核單鍊抗體抑制了α-突觸核蛋白於神經細胞內與細胞外的聚集作用，且也具有穿透血腦障蔽的能力，未來具有潛力應用於帕金森氏症的治療。 | zh_TW |
| dc.description.abstract | Parkinson’s disease (PD) is the most common movement disorder in the world. People suffering from the disease may have trouble such as moving or walking, tremor and difficult of balancing. One of the key pathologies is the formation of large plaques, Lewy Bodies, in substantia nigra (SN). The main component of the inclusions is alpha-syunclein (α-syn), a 14-20 kDa protein that accumulates in the neuronal cells, leading to the loss of cellular function and neuron death. It is now known that the mechanisms of α-syn toxicities is driven by mitochondria defects, endoplasmic reticulum (ER) stress, autophagic and lysosomal dysfunction, synaptic dysfunction, and so on. α-syn monomers, small dimers and oligomers are soluble pre-aggregated species that are considered to form toxic large oligomers and fibrils. Hence, these pre-aggregated species are demonstrated to participate in the pathogenesis.
In this study, we developed single-chain variable fragments (scFv) from chickens by phage-display techniques targeting α-syn monomers and oligomers. The result showed that our anti-α-syn scFvs have high binding affinity to both α-syn monomers and oligomers, and are able to inhibit the formation of aggregates in in vitro thioflavin –t (Th-t) aggregation assay. Besides, our anti-α-syn scFvs decreased the dimerization/oligomerization of α-syn in bimolecular fluorescence complementation (BiFC) assay in SH-SY5Y neuroblastoma cells. Our anti-α-syn scFvs also reduced the formation of α-syn monomers, dimers and trimers in MPP+-induced α-syn aggregation cell models. On the other hand, anti-G6 scFv antibody penetrated the blood-brain barrier after intravenous injection of the antibody to mice. In summary, we have developed high affinity anti-α-syn scFvs targeting α-syn monomers and oligomers, and reduced the accumulations in in vitro assays and cell models, which may become a potential therapeutic application for α-syn pathologies. | en |
| dc.description.provenance | Made available in DSpace on 2021-07-11T15:04:27Z (GMT). No. of bitstreams: 1 ntu-108-R06423016-1.pdf: 5325934 bytes, checksum: c4d50d77bf9fa8b3415cb8253df9d793 (MD5) Previous issue date: 2019 | en |
| dc.description.tableofcontents | 中文摘要 I
Abstract II Contents IV Abbreviations V List of figures VII List of tables IX Chapter 1 Introduction 1 Chapter 2 The aim of the study 29 Chapter 3 Material and methods 30 Chapter 4 Results 50 Chapter 5 Discussion 78 Chapter 6 Conclusion 82 Reference 83 | |
| dc.language.iso | en | |
| dc.subject | alpha突觸核蛋白 | zh_TW |
| dc.subject | 免疫療法 | zh_TW |
| dc.subject | 帕金森氏症 | zh_TW |
| dc.subject | 單鍊抗體 | zh_TW |
| dc.subject | single-chain variable fragments | en |
| dc.subject | immunotherapy. | en |
| dc.subject | alpha-synuclein | en |
| dc.subject | Parkinson’s disease | en |
| dc.title | 以噬菌體展現技術開發單鏈抗體抑制α-突觸核蛋白於神經細胞內聚集之探討 | zh_TW |
| dc.title | Phage display-derived single-chain variable fragments targeting alpha-synuclein monomers and oligomers inhibit the aggregation of alpha-synuclein in neuron cells | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 107-2 | |
| dc.description.degree | 碩士 | |
| dc.contributor.oralexamcommittee | 潘秀玲(Shiow-Lin Pan),李雨青(Yu-Ching Lee) | |
| dc.subject.keyword | 帕金森氏症,alpha突觸核蛋白,單鍊抗體,免疫療法, | zh_TW |
| dc.subject.keyword | Parkinson’s disease,alpha-synuclein,single-chain variable fragments,immunotherapy., | en |
| dc.relation.page | 92 | |
| dc.identifier.doi | 10.6342/NTU201903286 | |
| dc.rights.note | 有償授權 | |
| dc.date.accepted | 2019-08-16 | |
| dc.contributor.author-college | 醫學院 | zh_TW |
| dc.contributor.author-dept | 藥學研究所 | zh_TW |
| dc.date.embargo-lift | 2024-10-09 | - |
| 顯示於系所單位： | 藥學系 | |
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