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Volumn 56, Issue 3, 2004, Pages 319-328

Generalized brain and skin proteasome inhibition in Huntington's disease

Author keywords

[No Author keywords available]

Indexed keywords

BRAIN DERIVED NEUROTROPHIC FACTOR; HUNTINGTIN; NUCLEAR PROTEIN; PROTEASOME INHIBITOR; PROTEIN SUBUNIT; UBIQUITIN;

EID: 4444303263     PISSN: 03645134     EISSN: None     Source Type: Journal    
DOI: 10.1002/ana.20207     Document Type: Article
Times cited : (157)

References (50)
  • 1
    • 0034094873 scopus 로고    scopus 로고
    • Glutamine repeats and neurodegeneration
    • Zoghbi HY, Orr HT. Glutamine repeats and neurodegeneration. Annu Rev Neurosci 2000;23:217-247.
    • (2000) Annu Rev Neurosci , vol.23 , pp. 217-247
    • Zoghbi, H.Y.1    Orr, H.T.2
  • 2
    • 0034578144 scopus 로고    scopus 로고
    • Trinucleotide repeats: Mechanisms and pathophysiology
    • Cummings CJ, Zoghbi HY. Trinucleotide repeats: mechanisms and pathophysiology. Annu Rev Genomics Hum Genet 2000; 1:281-328.
    • (2000) Annu Rev Genomics Hum Genet , vol.1 , pp. 281-328
    • Cummings, C.J.1    Zoghbi, H.Y.2
  • 3
    • 0027480960 scopus 로고
    • A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington's disease chromosomes
    • The Huntington's Disease Study Group. Group. A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington's disease chromosomes. Cell 1993;72:971-983.
    • (1993) Cell , vol.72 , pp. 971-983
  • 4
    • 0027261537 scopus 로고
    • Relationship between trinucleotide repeat expansion and phenotypic variation in Huntington's disease
    • Snell RG, MacMillan JC, Cheadle JP, et al. Relationship between trinucleotide repeat expansion and phenotypic variation in Huntington's disease. Nat Genet 1993;4:393-397.
    • (1993) Nat Genet , vol.4 , pp. 393-397
    • Snell, R.G.1    MacMillan, J.C.2    Cheadle, J.P.3
  • 5
    • 0033080367 scopus 로고    scopus 로고
    • Glutamine repeats and neurodegenerative diseases: Molecular aspects
    • Perutz MF. Glutamine repeats and neurodegenerative diseases: molecular aspects. Trends Biochem Sci 1999;24:58-63.
    • (1999) Trends Biochem Sci , vol.24 , pp. 58-63
    • Perutz, M.F.1
  • 6
    • 0032904145 scopus 로고    scopus 로고
    • Intracellular inclusions, pathological markers in diseases caused by expanded polyglutamine tracts?
    • Rubinsztein DC, Wyttenbach A, Rankin J. Intracellular inclusions, pathological markers in diseases caused by expanded polyglutamine tracts? J Med Genet 1999;36:265-270.
    • (1999) J Med Genet , vol.36 , pp. 265-270
    • Rubinsztein, D.C.1    Wyttenbach, A.2    Rankin, J.3
  • 7
    • 85056013302 scopus 로고
    • Cortical and striatal neurone number in Huntington's disease
    • Heinsen H, Strik M, Bauer M, et al. Cortical and striatal neurone number in Huntington's disease. Acta Neuropathol (Berl) 1994;88:320-333,
    • (1994) Acta Neuropathol (Berl) , vol.88 , pp. 320-333
    • Heinsen, H.1    Strik, M.2    Bauer, M.3
  • 8
    • 0029055601 scopus 로고
    • Cellular localization of the Huntington's disease protein and discrimination of the normal and mutated form
    • Trottier Y, Devys D, Imbert G, et al. Cellular localization of the Huntington's disease protein and discrimination of the normal and mutated form. Nat Genet 1995;10:104-110.
    • (1995) Nat Genet , vol.10 , pp. 104-110
    • Trottier, Y.1    Devys, D.2    Imbert, G.3
  • 9
    • 0030919567 scopus 로고    scopus 로고
    • Oxidative damage and metabolic dysfunction in Huntington's disease: Selective vulnerability of the basal ganglia
    • Browne SE, Bowling AC, MacGarvey U, et al. Oxidative damage and metabolic dysfunction in Huntington's disease: selective vulnerability of the basal ganglia. Ann Neurol 1997;41: 646-653.
    • (1997) Ann Neurol , vol.41 , pp. 646-653
    • Browne, S.E.1    Bowling, A.C.2    MacGarvey, U.3
  • 10
    • 0036327065 scopus 로고    scopus 로고
    • Early mitochondrial calcium defects in Huntington's disease are a direct effect of polyglutamines
    • Panov AV, Gutekunst CA, Leavitt BR, et al. Early mitochondrial calcium defects in Huntington's disease are a direct effect of polyglutamines. Nat Neurosci 2002;5:731-736.
    • (2002) Nat Neurosci , vol.5 , pp. 731-736
    • Panov, A.V.1    Gutekunst, C.A.2    Leavitt, B.R.3
  • 11
    • 0034237719 scopus 로고    scopus 로고
    • Energetics in the pathogenesis of neurodegenerative diseases
    • Beal MF. Energetics in the pathogenesis of neurodegenerative diseases. Trends Neurosci 2000;23:298-304.
    • (2000) Trends Neurosci , vol.23 , pp. 298-304
    • Beal, M.F.1
  • 12
    • 0032900574 scopus 로고    scopus 로고
    • Biochemical abnormalities and excitotoxicity in Huntington's disease brain
    • Tabrizi SJ, Cleeter MW, Xuereb J, et al. Biochemical abnormalities and excitotoxicity in Huntington's disease brain. Ann Neurol 1999;45:25-32.
    • (1999) Ann Neurol , vol.45 , pp. 25-32
    • Tabrizi, S.J.1    Cleeter, M.W.2    Xuereb, J.3
  • 13
    • 0032826920 scopus 로고    scopus 로고
    • Cellular delivery of trophic factors for the treatment of Huntington's disease: Is neuroprotection possible?
    • Kordower JH, Isacson O, Emerich DF. Cellular delivery of trophic factors for the treatment of Huntington's disease: is neuroprotection possible? Exp Neurol 1999;159:4-20.
    • (1999) Exp Neurol , vol.159 , pp. 4-20
    • Kordower, J.H.1    Isacson, O.2    Emerich, D.F.3
  • 14
    • 0017167057 scopus 로고
    • Lesion of striatal neurones with kainic acid provides a model for Huntington's chorea
    • Coyle JT, Schwarcz R. Lesion of striatal neurones with kainic acid provides a model for Huntington's chorea. Nature 1976; 263:244-246.
    • (1976) Nature , vol.263 , pp. 244-246
    • Coyle, J.T.1    Schwarcz, R.2
  • 15
    • 0035862754 scopus 로고    scopus 로고
    • Expression of expanded repeat androgen receptor produces neurologic disease in transgenic mice
    • Abel A, Walcott J, Woods J, et al. Expression of expanded repeat androgen receptor produces neurologic disease in transgenic mice. Hum Mol Genet 2001;10:107-116.
    • (2001) Hum Mol Genet , vol.10 , pp. 107-116
    • Abel, A.1    Walcott, J.2    Woods, J.3
  • 16
    • 0033030565 scopus 로고    scopus 로고
    • Evidence for proteasome involvement in polyglutamine disease: Localization to nuclear inclusions in SCA3/MJD and suppression of polyglutamine aggregation in vitro
    • Chai Y, Koppenhafer SL, Shoesmith SJ, et al. Evidence for proteasome involvement in polyglutamine disease: localization to nuclear inclusions in SCA3/MJD and suppression of polyglutamine aggregation in vitro. Hum Mol Genet 1999;8:673-682.
    • (1999) Hum Mol Genet , vol.8 , pp. 673-682
    • Chai, Y.1    Koppenhafer, S.L.2    Shoesmith, S.J.3
  • 17
    • 0036198110 scopus 로고    scopus 로고
    • Protein surveillance machinery in brains with spinocerebellar ataxia type 3: Redistribution and differential recruitment of 26S proteasome subunits and chaperones to neuronal intranuclear inclusions
    • Schmidt T, Lindenberg KS, Krebs A, et al. Protein surveillance machinery in brains with spinocerebellar ataxia type 3: redistribution and differential recruitment of 26S proteasome subunits and chaperones to neuronal intranuclear inclusions. Ann Neurol 2002;51:302-310.
    • (2002) Ann Neurol , vol.51 , pp. 302-310
    • Schmidt, T.1    Lindenberg, K.S.2    Krebs, A.3
  • 18
    • 0035947372 scopus 로고    scopus 로고
    • Impairment of the ubiquitin-proteasome system by protein aggregation
    • Bence NF, Sampat RM, Kopito RR. Impairment of the ubiquitin-proteasome system by protein aggregation. Science 2001;292:1552-1555.
    • (2001) Science , vol.292 , pp. 1552-1555
    • Bence, N.F.1    Sampat, R.M.2    Kopito, R.R.3
  • 19
    • 0242531029 scopus 로고    scopus 로고
    • Inhibition of proteasomal activity causes inclusion formation in neuronal and nonneuronal cells overexpressing Parkin
    • Ardley HC, Scott GB, Rose SA, et al. Inhibition of proteasomal activity causes inclusion formation in neuronal and nonneuronal cells overexpressing Parkin. Mol Biol Cell 2003;14: 4541-4556.
    • (2003) Mol Biol Cell , vol.14 , pp. 4541-4556
    • Ardley, H.C.1    Scott, G.B.2    Rose, S.A.3
  • 20
    • 0033391428 scopus 로고    scopus 로고
    • Mutation of the E6-AP ubiquitin ligase reduces nuclear inclusion frequency while accelerating polyglutamine-induced pathology in SCA1 mice
    • Cummings CJ, Reinstein E, Sun Y, et al. Mutation of the E6-AP ubiquitin ligase reduces nuclear inclusion frequency while accelerating polyglutamine-induced pathology in SCA1 mice. Neuron 1999;24:879-892.
    • (1999) Neuron , vol.24 , pp. 879-892
    • Cummings, C.J.1    Reinstein, E.2    Sun, Y.3
  • 21
    • 0034703397 scopus 로고    scopus 로고
    • Identification and characterization of an ataxin-1-interacting protein: A1Up, a ubiquitin-like nuclear protein
    • Davidson JD, Riley B, Burright EN, et al. Identification and characterization of an ataxin-1-interacting protein: A1Up, a ubiquitin-like nuclear protein. Hum Mol Genet 2000;9: 2305-2312.
    • (2000) Hum Mol Genet , vol.9 , pp. 2305-2312
    • Davidson, J.D.1    Riley, B.2    Burright, E.N.3
  • 22
    • 0035430788 scopus 로고    scopus 로고
    • Failure of the ubiquitin-proteasome system in Parkinson's disease
    • McNaught KS, Olanow CW, Halliwell B, et al. Failure of the ubiquitin-proteasome system in Parkinson's disease. Nat Rev Neurosci 2001;2:589-594.
    • (2001) Nat Rev Neurosci , vol.2 , pp. 589-594
    • McNaught, K.S.1    Olanow, C.W.2    Halliwell, B.3
  • 23
    • 0037193469 scopus 로고    scopus 로고
    • Mutant ubiquitin found in neurodegenerative disorders is a ubiquitin fusion degradation substrate that blocks proteasomal degradation
    • Lindsten K, de Vrij FM, Verhoef LG, et al. Mutant ubiquitin found in neurodegenerative disorders is a ubiquitin fusion degradation substrate that blocks proteasomal degradation. J Cell Biol 2002;157:417-427.
    • (2002) J Cell Biol , vol.157 , pp. 417-427
    • Lindsten, K.1    De Vrij, F.M.2    Verhoef, L.G.3
  • 24
    • 0036566266 scopus 로고    scopus 로고
    • Aggregate-prone proteins with polyglutamine and polyalanine expansions are degraded by autophagy
    • Ravikumar B, Duden R, Rubinsztein DC. Aggregate-prone proteins with polyglutamine and polyalanine expansions are degraded by autophagy. Hum Mol Genet 2002;11:1107-1117.
    • (2002) Hum Mol Genet , vol.11 , pp. 1107-1117
    • Ravikumar, B.1    Duden, R.2    Rubinsztein, D.C.3
  • 26
    • 0037137702 scopus 로고    scopus 로고
    • Parkin protects against the toxicity associated with mutant alpha-synuclein: Proteasome dysfunction selectively affects catecholaminergic neurons
    • Petrucelli L, O'Farrell C, Lockhart PJ, et al. Parkin protects against the toxicity associated with mutant alpha-synuclein: proteasome dysfunction selectively affects catecholaminergic neurons. Neuron 2002;36:1007-1019.
    • (2002) Neuron , vol.36 , pp. 1007-1019
    • Petrucelli, L.1    O'Farrell, C.2    Lockhart, P.J.3
  • 27
    • 0041353535 scopus 로고    scopus 로고
    • Huntingtin interacts with REST/NRSF to modulate the transcription of NRSE-controlled neuronal genes
    • Zuccato C, Tartari M, Crotti A, et al. Huntingtin interacts with REST/NRSF to modulate the transcription of NRSE-controlled neuronal genes. Nat Genet 2003;35:76-83.
    • (2003) Nat Genet , vol.35 , pp. 76-83
    • Zuccato, C.1    Tartari, M.2    Crotti, A.3
  • 28
    • 0035919701 scopus 로고    scopus 로고
    • Loss of huntingtin-mediated BDNF gene transcription in Huntington's disease
    • Zuccato C, Ciammola A, Rigamonti D, et al. Loss of huntingtin-mediated BDNF gene transcription in Huntington's disease. Science 2001;293:493-498.
    • (2001) Science , vol.293 , pp. 493-498
    • Zuccato, C.1    Ciammola, A.2    Rigamonti, D.3
  • 30
    • 0030926777 scopus 로고    scopus 로고
    • Lactacystin and clasto-lactacystin beta-lactone modify multiple proteasome beta-subunits and inhibit intracellular protein degradation and major histocompatibility complex class I antigen presentation
    • Craiu A, Gaczynska M, Akopian T, et al. Lactacystin and clasto-lactacystin beta-lactone modify multiple proteasome beta-subunits and inhibit intracellular protein degradation and major histocompatibility complex class I antigen presentation. J Biol Chem 1997;272:13437-13445.
    • (1997) J Biol Chem , vol.272 , pp. 13437-13445
    • Craiu, A.1    Gaczynska, M.2    Akopian, T.3
  • 31
    • 0018199057 scopus 로고
    • Preparation and characterization of mitochondria and submitochondrial particles of rat liver and liver-derived tissues
    • Pedersen PL, Greenawalt JW, Reynafarje B, et al. Preparation and characterization of mitochondria and submitochondrial particles of rat liver and liver-derived tissues. Methods Cell Biol 1978;20:411-481.
    • (1978) Methods Cell Biol , vol.20 , pp. 411-481
    • Pedersen, P.L.1    Greenawalt, J.W.2    Reynafarje, B.3
  • 32
    • 0029918289 scopus 로고    scopus 로고
    • A role for the proteasome regulator PA28alpha in antigen presentation
    • Groettrup M, Soza A, Eggers M, et al. A role for the proteasome regulator PA28alpha in antigen presentation. Nature 1996;381:166-168.
    • (1996) Nature , vol.381 , pp. 166-168
    • Groettrup, M.1    Soza, A.2    Eggers, M.3
  • 33
    • 0034353223 scopus 로고    scopus 로고
    • The proteasome regulator PA28alpha/beta can enhance antigen presentation without affecting 20S proteasome subunit composition
    • Schwarz K, Eggers M, Soza A, et al. The proteasome regulator PA28alpha/beta can enhance antigen presentation without affecting 20S proteasome subunit composition. Eur J Immunol 2000;30:3672-3679.
    • (2000) Eur J Immunol , vol.30 , pp. 3672-3679
    • Schwarz, K.1    Eggers, M.2    Soza, A.3
  • 34
    • 0031743608 scopus 로고    scopus 로고
    • Self-inactivating lentivirus vector for safe and efficient in vivo gene delivery
    • Zufferey R, Dull T, Mandel RJ, et al. Self-inactivating lentivirus vector for safe and efficient in vivo gene delivery. J Virol 1998;72:9873-9880.
    • (1998) J Virol , vol.72 , pp. 9873-9880
    • Zufferey, R.1    Dull, T.2    Mandel, R.J.3
  • 35
    • 0034595722 scopus 로고    scopus 로고
    • Brain-derived neurotrophic factor in Huntington disease
    • Ferrer I, Goutan E, Marin C, et al. Brain-derived neurotrophic factor in Huntington disease. Brain Res 2000;866:257-261.
    • (2000) Brain Res , vol.866 , pp. 257-261
    • Ferrer, I.1    Goutan, E.2    Marin, C.3
  • 36
    • 15144351709 scopus 로고    scopus 로고
    • Differential distribution of the normal and mutated forms of huntingtin in the human brain
    • Gourfinkel-An I, Cancel G, Trottier Y, et al. Differential distribution of the normal and mutated forms of huntingtin in the human brain. Ann Neurol 1997;42:712-719.
    • (1997) Ann Neurol , vol.42 , pp. 712-719
    • Gourfinkel-An, I.1    Cancel, G.2    Trottier, Y.3
  • 37
    • 0034646426 scopus 로고    scopus 로고
    • Effects of heat shock, heat shock protein 40 (HDJ-2), and proteasome inhibition on protein aggregation in cellular models of Huntington's disease
    • Wyttenbach A, Carmichael J, Swartz J, et al. Effects of heat shock, heat shock protein 40 (HDJ-2), and proteasome inhibition on protein aggregation in cellular models of Huntington's disease. Proc Natl Acad Sci USA 2000;97:2898-2903.
    • (2000) Proc Natl Acad Sci USA , vol.97 , pp. 2898-2903
    • Wyttenbach, A.1    Carmichael, J.2    Swartz, J.3
  • 38
    • 0036580677 scopus 로고    scopus 로고
    • Lentiviral-mediated delivery of mutant huntingtin in the striatum of rats induces a selective neuropathology modulated by polyglutamine repeat size, huntingtin expression levels, and protein length
    • de Almeida LP, Ross CA, Zala D, et al. Lentiviral-mediated delivery of mutant huntingtin in the striatum of rats induces a selective neuropathology modulated by polyglutamine repeat size, huntingtin expression levels, and protein length. J Neurosci 2002;22:3473-3483.
    • (2002) J Neurosci , vol.22 , pp. 3473-3483
    • De Almeida, L.P.1    Ross, C.A.2    Zala, D.3
  • 39
    • 0033529596 scopus 로고    scopus 로고
    • The proteasome, a novel protease regulated by multiple mechanisms
    • DeMartino GN, Slaughter CA. The proteasome, a novel protease regulated by multiple mechanisms. J Biol Chem 1999; 274:22123-22126.
    • (1999) J Biol Chem , vol.274 , pp. 22123-22126
    • DeMartino, G.N.1    Slaughter, C.A.2
  • 40
    • 0030016595 scopus 로고    scopus 로고
    • Structure and functions of the 20S and 26S proteasomes
    • Coux O, Tanaka K, Goldberg AL. Structure and functions of the 20S and 26S proteasomes. Annu Rev Biochem 1996;65:801-847.
    • (1996) Annu Rev Biochem , vol.65 , pp. 801-847
    • Coux, O.1    Tanaka, K.2    Goldberg, A.L.3
  • 41
    • 0347064159 scopus 로고    scopus 로고
    • Neuronal induction of the immunoproteasome in Huntington's disease
    • Diaz-Hernandez M, Hernandez F, Martin-Aparicio E, et al. Neuronal induction of the immunoproteasome in Huntington's disease. J Neurosci 2003;23:11653-11661.
    • (2003) J Neurosci , vol.23 , pp. 11653-11661
    • Diaz-Hernandez, M.1    Hernandez, F.2    Martin-Aparicio, E.3
  • 42
    • 0037134460 scopus 로고    scopus 로고
    • Polyglutamine expansion, protein aggregation, proteasome activity, and neural survival
    • Ding Q, Lewis JJ, Strum KM, et al. Polyglutamine expansion, protein aggregation, proteasome activity, and neural survival. J Biol Chem 2002;277:13935-13942.
    • (2002) J Biol Chem , vol.277 , pp. 13935-13942
    • Ding, Q.1    Lewis, J.J.2    Strum, K.M.3
  • 43
    • 0038413759 scopus 로고    scopus 로고
    • Aggregated and monomeric alpha-synuclein bind to the S6′ proteasomal protein and inhibit proteasomal function
    • Snyder H, Mensah K, Theisler C, et al. Aggregated and monomeric alpha-synuclein bind to the S6′ proteasomal protein and inhibit proteasomal function. J Biol Chem 2003;278: 11753-11759.
    • (2003) J Biol Chem , vol.278 , pp. 11753-11759
    • Snyder, H.1    Mensah, K.2    Theisler, C.3
  • 44
    • 0034754875 scopus 로고    scopus 로고
    • Accumulation of mutant huntingtin fragments in aggresome-like inclusion bodies as a result of insufficient protein degradation
    • Waelter S, Boeddrich A, Lurz R, et al. Accumulation of mutant huntingtin fragments in aggresome-like inclusion bodies as a result of insufficient protein degradation. Mol Biol Cell 2001; 12:1393-1407.
    • (2001) Mol Biol Cell , vol.12 , pp. 1393-1407
    • Waelter, S.1    Boeddrich, A.2    Lurz, R.3
  • 45
    • 0034537528 scopus 로고    scopus 로고
    • Neurotrophic factors NGF and FGF-2 alter levels of huntingtin (IT15) in striatal neuronal cell cultures
    • Haque NS, Isacson O. Neurotrophic factors NGF and FGF-2 alter levels of huntingtin (IT15) in striatal neuronal cell cultures. Cell Transplant 2000;9:623-627.
    • (2000) Cell Transplant , vol.9 , pp. 623-627
    • Haque, N.S.1    Isacson, O.2
  • 46
    • 0035139276 scopus 로고    scopus 로고
    • Expression of brain-derived neurotrophic factor in cortical neurons is regulated by striatal target area
    • Canals JM, Checa N, Marco S, et al. Expression of brain-derived neurotrophic factor in cortical neurons is regulated by striatal target area. J Neurosci 2001;21:117-124.
    • (2001) J Neurosci , vol.21 , pp. 117-124
    • Canals, J.M.1    Checa, N.2    Marco, S.3
  • 47
    • 0031004888 scopus 로고    scopus 로고
    • Distribution of brain-derived neurotrophic factor (BDNF) protein and mRNA in the normal adult rat CNS: Evidence for anterograde axonal transport
    • Conner JM, Lauterborn JC, Yan Q, et al. Distribution of brain-derived neurotrophic factor (BDNF) protein and mRNA in the normal adult rat CNS: evidence for anterograde axonal transport. J Neurosci 1997;17:2295-2313.
    • (1997) J Neurosci , vol.17 , pp. 2295-2313
    • Conner, J.M.1    Lauterborn, J.C.2    Yan, Q.3
  • 48
    • 1842334441 scopus 로고    scopus 로고
    • Anterograde transport of brain-derived neurotrophic factor and its role in the brain
    • Altar CA, Cai N, Bliven T, et al. Anterograde transport of brain-derived neurotrophic factor and its role in the brain. Nature 1997;389:856-860.
    • (1997) Nature , vol.389 , pp. 856-860
    • Altar, C.A.1    Cai, N.2    Bliven, T.3
  • 49
    • 0033544840 scopus 로고    scopus 로고
    • Brain-derived neurotrophic factor-mediated protection of striatal neurons in an excitotoxic rat model of Huntington's disease, as demonstrated by adenoviral gene transfer
    • Bemelmans AP, Horellou P, Pradier L, et al. Brain-derived neurotrophic factor-mediated protection of striatal neurons in an excitotoxic rat model of Huntington's disease, as demonstrated by adenoviral gene transfer. Hum Gene Ther 1999;10:2987-2997.
    • (1999) Hum Gene Ther , vol.10 , pp. 2987-2997
    • Bemelmans, A.P.1    Horellou, P.2    Pradier, L.3
  • 50
    • 0029875381 scopus 로고    scopus 로고
    • Mitochondrial defect in Huntington's disease caudate nucleus
    • Gu M, Gash MT, Mann VM, et al. Mitochondrial defect in Huntington's disease caudate nucleus. Ann Neurol 1996;39: 385-389.
    • (1996) Ann Neurol , vol.39 , pp. 385-389
    • Gu, M.1    Gash, M.T.2    Mann, V.M.3


* 이 정보는 Elsevier사의 SCOPUS DB에서 KISTI가 분석하여 추출한 것입니다.