45 22 2000 11 * (, 100083 * ),,, (Parkinson s disease, PD) (dopamine, DA) Lewy (Lewy s body, LB), PD PD 02%, 55 14%, 75 34% [1],, PD 3 4, 6, 2, PD,, 1 PD 3 PD 1 4 q21-q23, α -Synuclein [2] 209 G-A, 53 (Ala) (Thr) α-synuclein PD LB, PD 2 PD PD (autosomal recessive juvenile parkinsonism, ARJP) 6 q252~q27, D6S305 D6S253 [3] 2 960, 1 395, 465, parkin, 3 PD 2P13, Park3 [4] Park3, 3 PD PD, PD, PD, PD 1983, PD, 1- -4-1, 2, 3, 6- (1-methyl-4-phenyl-1, 2, 3,6-tetrahydropyridine, MPTP) [5] PD PD 2366
45 22 2000 11 MPTP, MPTP DA [6], PD, PD PD PD P450 2D6 (CYP2D6) (glutathione S-transferase, GSTM1), PD, PD 10~14 [7], PD PD PD, 50, PD, PD 2 PD LB LB, LB 7~25 nm,, 3, : α-synuclein [8] LB 4 : LB ; LB ; LB ; PD LB, LB 3 (1) PD DA,, [9] :, ;, ;, (2), NMDA AMPA DA NMDA AMPA NMDA, Ca 2+ Ca 2+, NMDA, NO [10], PD DNA GSH( ), (3) [11] ATP, 1- - 4 (1-methyl-4-phenylpyridinium, MPP ),, 18 P113 ( 2367
45 22 2000 11 NADH ), PD C-T, 29, PD [12] (4) (dopamine transporter, DAT) (vesicular monoamine transporter, VMAT2) PD [13], DA, DAT DA [14] DAT,, VMAT2,, DAT MPTP DAT, MPTP DA [15] VMAT2 2, VMAT2, MPTP DA 1 [16] DAT VMAT2 DA, PD, PD,,,, PD 4, PD, 75,, DA, DA, DA DA, DAT DA DA, DAT DA DAT DA ( D 2 ), PD DA, PD (1) (single photon emission computed tomography, SPECT) DAT DA, DA, DAT DA, DAT, DAT SPECT PD DAT, DA, DAT β-cit(2-β-carbomethoxy-3-β-4- iodophenyl- tropane) FP-CIT [17, 18] β- CIT FP-CIT DAT, 24 h 3 h 123 I-β-SPECT PD DAT, 2368
45 22 2000 11 PD DAT, PD ; PD DAT [19] PD 80% DA 40% DA [20] PD PD SPECT, (2) (positron emission tomography, PET) 18 F-DOPA PET,, 18 F-DOPA, DA, PD, PET 18 F-DOPA SPECT DAT [21] PD SPECT PD, PET 18 F -DOPA, - DA,,, 5 L-DOPA PD,, DA (1) DA (nerve growth factor, NGF) neurotrophic factor, BDNF) (neurotrophin-4/5, NT-4/5) -3(neurtrophin-3, NT-3) (brain-derived / (glial cell line-derived neurotrophic factor, GDNF) neurturin(ntn) (basic fibroblast growth neurotrophic factor) -β(transforming growth factor-β) [22, 23] GDNF GDNF 1 65 PD,,, [24], PD GDNF (2) (immunophilin), A(CsA) FK506 CsA FK506,,,, CsA FK506 -,, FK506 [25] ( DA ), PD (3) DA 2369
45 22 2000 11 - DA (mitochondrial megachannel), - [26] 6 2370, PD 90,, PD, PD, PD,,,,, VIM [27], CT( ) MRI( ),, PD, PD L-DOPA ; PD 7 (1) 1) 1990,, DA 2~3 [28], 2), DA 28 d DA TH, PD, [29], 3), DA,, DA,, (bfgf EGF), DA, DA PD [30] 60, PD,,
45 22 2000 11 (2) 1) DA,, NGF [31] 2) PC12 DA DA, 1991 PC12 PD, PD [32] 3) DA, PD [33],, DA, GABA, DA, DA, PD, PD 8 : 1) DA DA (tyrosine hydroxylase, TH) DA, TH PD 2) DA, GDNF BDNF, NGF NT-3,, (1) TH DA, TH PD TH, DA, TH in vivo ex vivo TH TH PD TH; TH, TH, ( ) TH, PD [34] Tornatore, TH cdna TH, PD, [35] TH,, PD,, [36] TH, [37] PD, (2) GTP 1 TH BH4( ), 2371
45 22 2000 11 BH4, TH BH4 GTP 1, L-DOPA [38] (3) (aromatic L-amino acid decarboxylase, AADC) L-DOPA DA AADC 98%TH 80%~85% AADC, AADC L-DOPA DA [39] AADC, AADC 10~400 [40] PD AADC TH AADC, DA TH, TH AADC 6-OHDA, TH [41] AADC 6-OHDA, L-DOPA AADC DA 6 [42] (4) DA, GDNF, BDNF NGF GDNF GDNF PD [43] BDNF PD [44] Rohrer [45] NGF, PC12,,,, TH, NGF, PC12, 2 NGF DA,, bcl-2, bcl-x -2(vesicular monoamine transporter-2, VMAT-2) PD, (5), PD, PD ( ) TH GDNF DA, MPP DA, 9 PD,, PD, Feany, α -Synuclein PD, 30~60 d DA, LB α -Synuclein [46] LB PD, PD,, α-synuclein PD PD 1, PD PD PD, DNA, PD α-synuclein PD LB, LB 2372
45 22 2000 11 PD PD, α -Synuclein PD PD,, PD, DAT PD, PD, PD, PD PD DA ; PD, PD PD,, [47] ( : ) ;, DA ; ;,, PD, [48],,, PD PD PD,, PD 973 ( : G1999054008) ( : 96-906-05-08) ( : 39970924) 1 Wood N Genes and Parkinsonism J Neurol Neurosurg Psychiatry, 1997, 62: 305~309 2 Polymeropoulos M H, Higgins J J, Globe L I, et al Mapping of a gene for Parkinson s disease to chromosome 4q21-q23 Science, 1996, 276: 2045~2047 3 Tohru Kitada, Shuichi Asakawa, Nobutaka Hattori, et al Mutations in the Parkin gene cause autosomal recessive juvenile Parkinsonism Nature, 1998, 392: 605~608 4 Gasser T, Muller-Myhsok B, Wszolek Z K A susceptibility locus for Parkinson s disease to chromosome 2P13 Nat Genet, 1998, 18: 262~265 5 Calne D B, Langston J W Aetiology of Parkinson s disease Lancet, 1983, 2: 1457~1459 6 Langston J W Epidemiology verus genetics in Parkinson s disease: progress in resolving an age-old debate Ann Neurol, 1998, 44(Suppl): S45~62 7 Nicholl D J, Bennet P, hiller L, et al A study of five candidate gene in Parkinson s disease and related neurodegenerative disorders Neurology, 1999, 53(7): 1415~1421 8 Hill W D, Lee V M Y, Hurtig H I, et al Epitopes located in spatially separate domains of each neurofilament subunit are 2373
45 22 2000 11 present in Parkinson s disease Lewy bodies J Comp Neurol, 1991, 309: 150~160 9 Dexter D T, Sian J, Rose S, et al Indices of oxidative stress and mitochndrial function in individuals with incidental Lewy body disease Ann Neurol, 1994, 35: 38~44 10 Heales S J, Bolanos J P, Stewart V C, et al Nitric oxide, mitochondria and neurological disease Biochim Biophys Acta, 1999, 1410: 215~228 11 Mizuno Y in Movement disorders Neurological Principles and Practices (Watts R L, Koller W C eds), New York: Mcgraw- Hill, 1997 161~182 12 Hattori N, Yoshino H, Tanaka M, et al Allele in the 24-kDa subunit gene (NDUFV2) of mitochondrial complex I and susceptibility to PD Genomics, 1998, 49: 52~58 13 Marsden C D, Olanow C W The causes of Parkinson s disease are being unraveled and rational neuroprotectic therapy is close to reality Ann Neurol, 1998, 44(Suppl): S155~159 14 Javitch J, Amato R, Strittmatter S, et al Parkinsonism-inducing neurotoxin N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine: up-take of the metabolite N-methyl- 4-phenylpyridine by dopamainergic neurons explains selective neurotoxicity Proc Natl Acad Sci USA, 1985, 82: 2173~2177 15 Gainelinov R R, Fumagalli F, Jones S R, et al Dopamine transporter required for in vivo MPTP neurotoxicity: evidence from mice lacking the transporter J Neurochem, 1997, 69: 1322~1325 16 Takaloshi N, Miner L, Sora L, et al VMAT2 knockout mice: heterozygotes display reduced amphetamine-conditioned reward enhanced amphetamine locomotion, and enhance MP TP toxicity Proc Natl Acad Sci USA, 1997, 94: 9938~9943 17 Booij J, Tissingh G, Boer G J, et al [123I]FP-CIT SPECT shows pronounced decline of striatal dopamine transporter labeling in early and advanced Parkinson s disease J Neurosurg Psychiatry, 1997, 62: 133~140 18 Tissingh G, Bergmans P, Booij J, et al [123I]-beta-CIT SPECT in Parkinson s disease reveals a smaller decline in dopamine transporters with age than in controls Eur J Nucl Med, 1997, 24: 1171~1174 19 Vermeulen R J, Wolters E C, Tissingh G, et al Evaluation of [123I]-beta-CIT binding with SPECT in controls, early and late Parkinson s disease Nucl Med Biol, 1995, 22: 985~991 20 Kish S J, Shannak K, Hornykiewicz O Uneven pattern of dopamine loss in the striatum of patients with idiopathic Parkinson s disease, pathophysiologic and clinical implications N Engl J Med, 1988, 876: 876~880 21 Morrish P K, Sawle G V, Brooks D J Clinical and [ 18 F]DOPA PET findings in early Parkinson s disease J Neurol Neurosurg Psychiatry, 1995, 59: 600~697 22 Hagg T Neurotrophins prevent death and differentially affect tyrosine hydroxylase of adult rat nigrostriatal neurons in vivo Exp Neurol, 1998, 149: 183~192 23 Unsicker K, Suter-Crazzolara C, Krieglstein K Growth factor function in the development and maintenance of midbrain dopaminergic neurons: concepts, facts and prospects for TGF-β Ciba Found Symp, 1996, 196: 70~80 24 Kordower J H, Alfi S, Chen E Y, et al Clinicopathological findings following intraventricular glial-derived neurotrophic factor treatment in a patient with Parkinson s disease Ann Neurol, 1999, 46: 419~424 25 Steiner J P, Hamilton G S, Ross D T, et al Neurotrophic immunophilin ligands stimulate structural and functional recovery in neurodegenerative animal models Proc Natl Acad Sci USA, 1997, 94: 2019~2124 26 Green D R, Reed J C Mitochondria and apoptosis Science, 1999, 281: 1309~1312 27 Iacono R P, Shima F, Lonser R R, et al The results, indications and physiology of posteroventral pallidotomy for patients with Parkinson s disease Neurosurgery, 1995, 36: 1118~1127 28 Olanow C W, Freman T B, Kordower J H Neural transplantation as a therapy for Parkinson s disease Adv Neurol, 1997, 74: 249~269 2374
45 22 2000 11 29 Molenaar G J, Hogenesch R I, Sprengers M E, et al Ontogensis of embryonic porine ventral mesencephalon in the perspective of its potential use as a xenograft in Parkinson s disease J Comp Neurol, 1997, 382: 19~28 30 Ling Z D, Potter E D, Lipton J W, et al Differentiation of mesencephalic progenitor cells into dopaminergic neurons by cytokines Exp Neurol, 1998, 149: 411~423 31 Date I, Ohmoto T Neural transplantation for Parkinson s disease Cellular and Mol Neurobio, 1999, 19: 67~78 32 Aebischer P, Tresco P A, Sagen J, et al Transplantation of microencapsulated bovine chromaffin cells reduces lesion induced rotational asymmetry in rats Brain Res, 1991, 560: 43~49 33 Espejo E F, Montoro R J, Armengol J A, et al Cellular and functional recovery of Parkinsonian rats after intrastriatal transplantation of carotid body cell aggregates Neuron, 1998, 20: 197~206 34 Ahlskog J E Cerebral transplantation for Parkinson s disease: current progress and future prospects Mayo Clin Proc, 1993, 68: 578~591 35 Tornatore C, Baker-Cairns B, Yadid G Expression of tyrosine hydroxylase in an immortalized human fetal astrocyte cell line, in vitro characterization and engraftment into the rodent striatum Cell Transplant, 1996, 5(2): 145~163 36,,, TH : :, 1999 289 37 Chen S D, Zhao Y C, Liu Z G, et al Gene therapy in Parkinsonian rats by genetically modified myoblast expressing tyrosine hydroxylase Movement Disorders, 1997, 12(suppl): 81 38 Leff S E, Rendahl K G, Spratt S K, et al In vivo L-DOPA production by genetically modified primary rat fibroblast or 9L gliosarcoma cell grafts via coexpression of GTP cyclohydrolase I with tyrosine hydroxylase Exp Neurol, 1998, 151: 249~264 39 Hefti F, Melamed E, Wurtman R J The site of dopamine formation in rat striatum after L-DOPA administration J Pharmac Exp Ther, 1981, 217: 189~197 40 Bowsher R R, Henry D P Aromatic L-amino acid decarboxylase In: Boulton A A, Baker G B, Yu P H, eds Neurotransmitter Enzymes NJ: Humana, Clifton, 1986 33~78 41 Imaoka T, Date I, Dhmoto T, et al Significant behavioral recovery in Parkinson's disease model by direct intracerebral gene transfer using continuous injection of a plasmid DNA-liposome complex Hum Gene Ther, 1998, 9: 1093~1102 42 Leff S E, Spratt S K, Snyder R O, et al Long-term restoration of striatal L-aromatic amino acid decarboxylase activity using recombinant adeno-associated viral vector gene transfer in a rodent model of Parkinson s disease Neurosci, 1999, 92(1): 185~196 43 Mandel R J, Spratt S K, Snyder R O Midbrain injection of recombinant adeno-associated neurotrophic virus encoding rat glial cell line-derived neurotrophic factor protects nigral neurons in a progressive 6-hydroxydopamine-induced degeneration and behavioral impairment in a rat model of Parkinson s disease in rats Proc Natl Acad Sci USA, 1997, 94: 14083~14088 44 Yoshimoto Y, Lin Q, Collier T J, et al Astrocytes retrovirally transduced with BDNF elicits behavioral improvement in a rat model of Parkinson s disease Brain Res, 1995, 691(1-2): 25~36 45 Rohrer D C, Nilaver G, Nipper V, et al Genetically modified PC12 brain grafts: survivability and inducible nerve growth factor expression Cell Transplant, 1996, 5(1): 57~68 46 Feany M B, Bender W W A Drosophila model of Parkinson s disease Nature, 2000, 404: 394~398 47 Barinaga M Fetal neuron grafts pave the way for stem cell therapies Science, 2000, 287(5457): 1421~1422 48 Constantini L C, Bakowska J C, Breakefield X O, et al Gene therapy in the CNS Gene Therapy, 2000, 7: 93~109 (2000-04-20, 2000-07-26 ) 2375