2002-2003 > Academic research: refereed > Publication in refereed journalVersion of RecordPublishe

Guo, SY

Li, L

Qian, ZM

Wang, K

Wang, W

2002-2003 > Academic research: refereed > Publication in refereed journalVersion of RecordPublishedVoR allowe

PolyU Institutional Repository

·特邀综述·????????????钱忠明(??????????????????????? , ??)????　钱忠明 ,江苏苏州人。1978年毕业于苏州医学院医疗系 ,1981年获北京大学医学部(原北京医科大学)基础医学系病理生理学硕士学位 , 1993年获澳大利亚西澳大利亚大学(Universityof Western Australian)生理学博士学位。同年应聘到香港理工大学应用生物和化学科技学系任职讲师(Lecturer)。1998年任职助理教授(Assistant Professor), 1999年起任职副教授(Associate Pro-fessor)。主要从事脑铁代谢机制 、脑铁代谢异常与神经变性性疾病关系的研究 。曾应邀为《BrainResearch Review s》 、《Trends in Molecular Medicine》 、《Trends in Pharmacological Sciences》 、《Prog ressin Biophysics and Molecular Biology》 、《Developmental Neuroscience》和《Cellular and Molecular Biolo-gy》等 SCI 杂志撰写综述 、评论或研究论文等 。至今在国内外杂志发表论文 110余篇 ,主编了第一部《铁代谢 ———基础与临床》中文专著。??　最近关于脑铁代谢研究的新成果 ,尤其是与脑铁转运 、储存 、调节相关的某些突变基因的发现 ,足以得出以下结论 ,即异常增高的脑铁至少是部份神经变性性疾病的起始原因。研究显示 ,脑铁过量积聚主要是由于遗传性和非遗传性因素所引起的某些脑铁代谢蛋白功能异常或表达失控。正是异常增高的脑铁触发一系列病理反应 ,最终导致神经变性性疾病病人脑神经元死亡。本文简要叙述了目前对脑铁分布 、功能和脑铁代谢蛋白的认识 ,讨论了脑内铁转运机制以及脑铁和神经变性性疾病之间的关系研究的新进展 。???　铁代谢;脑铁;神经退行性变?????　Q42;R338Brain Iron Metabolism and Neurodegenerative Diseases　Q IAN Zhong-M ing (Laboratory of IronMetabolism , Department of Applied Biology &Chemical Technology , the Hong Kong Poly technicUniversi ty , Kow loon , Hong Kong)Abstract　New findings from recent studies on brain i ron metabolism , especially the discovery of mu-tations in the genes associated w ith iron t ransport , storage or regulation in the brain , are more than e-nough to conclude that the increased brain i ron is an initial cause of neuronal death at least in some neu-rodegenerat ive diseases.The excess iron accumulation in the brain may lead by the disrupted expres-sion o r function of i ron metabolism proteins induced by either genetic or nongenet ic factors.It is theincreased brain iron that t riggers a cascade of deleterious events , leading to neuronal death in these dis-orders.In this article , the recent advances in the study on mechanisms of iron t ranspo rt in the brainand the relationship between the increased brain iron and neurodegenerative disorders were discussed.Also , current knowledge on brain iron dist ribution and function w as brief ly review ed.Key words　Iron metabolism;Brain iron;Neurodegeneration　　?????????????? 19 ??? 。1886 ? , Zaleski ????????????? 。1922? , Spatz ??????? 128?????????????。????????????????????。??????????????????? 。???????????? ,????·197·?????? 2002?? 33?? 3?????????? ,?????????? 。?? ,?????????????????????? ,?????????? 。????????? ,???????????????。????20?? ,??????????????。???????????????????????????????????? ,??????????????? 。???? ,???????????????????????????????????????????? 。?????????????????????????????????。?????????????? 、?????????? ,????????????????????????????????????。? 、???? 、??????????????????? ,????????[ 1] 。???????? 、?? 、??????????????。??????????? ,??????????。???????????? 。???????????? 1/5。????? ,???????????? ,???? 、????? 、??????????????。?? ,????????????。???????????。???????? ,???? 、?? 、?????????????????? ,?????? ,?? 17??????。??????????? 75? ,?????????????????? 。?????????????????? ,??????????????????? ,????????????????? 。????????????20?????????? , 30??????????;???????? 50 ～ 60??????????。?????? ,??????????;???? 、?????;???????????。?????????????。??????????????????? ,?????????????????????。???????????? ,?? ,???????? ,?????????????????????? ,?????????????[ 1] 。??????????????? 。???????? ,???????????????????。???????? ,????????????????? , ?? DNA 、RNA ??????? ,????????????????? ,?????????????[ 2] 。?????? ,???????????????????????????。????????????????????? ,????????????。?? ,?????????????????????????[ 1] 。?????????????? ,???????????????? ,????????????????? 。??? ,??????????????????:??????(t ransferrin re-ceptor , TfR)????(ferritin)。??????????????? 。??????????? ,?????????????????(iron regulatoryprotein , IRP)? TfR? Ferritin mRNA ???????(iron response element , IRP)???????????????? ,?????????????? 。?????????? , IRP ? IRE ????? NO(ni tric oxide)?????????[ 3 ～ 5] 。???? TfR????? Ferritin???? ,????[ 2] 。TfR???? ,????????。????????? TfR????????????????。?????????????????(transferrin , Tf)???(transferrin-bound iron , Tf-Fe)。????? Tf???????????。????????????? TfR??????????[ 6] 。???? ,????? TfR? Ferritin ,???????????? IRP/ IRP ??。???? ,TfR????? Tf-Fe ?????????????????[ 2 , 7～ 10] 。?? ,??????????????????????????。??TfR 、Ferri tin? ,????????????? ,????????(lactoferrin receptor , LfR)、p97(melanot ransferrin ,? human melanoma tumor-asso-ciated antigen)???????? (divalent metalt ranspo rter , DMT1 ? divalent cation transporter ,DCT ? natual resistance-associated macrophage pro-tein 2 , N ramp2)。??????????????????????????[ 2 , 11] 。?? ,???????????? ferroportin(FP1)[ 12] 、hephaestin(HP)[ 13]? duodenal cy tochrome b(Dcy tb)[ 14]????????????????? 。? 、????????(?)???????(BBB)???　????·198· ?????? 2002?? 33?? 3????BBB ,?????????????。?? ,????????????? BBB? 。?? ,??????????-?????????(Tf/TfR)?????????????(luminal membrane)????? 。?????????? Tf-Fe????????????????? ,???? Tf???。????????????????????????[ 11] 。?????????:?? 、?? 、????? 、???????? 。???? Tf???(Tf-Fe)? BBB ,??? BBB ??????? TfR?? ,?? TfR???????????。???????? H +?????????? pH ????? 5.5 ～ 6.5 ,????? Tf??????Fe2+。??? DMT1????? , Fe2+????????????????? 。??? Tf? TfR?????????????。? pH 7.4 ???? , Tf ?TfR?????????[ 11 ,15] 。???????????? Fe2+??????????????????(abluminal membrane)????(? 1)[ 11] 。??????????????? 。????Fe2+??????????????????。?????????????????????????? Fe2+???。???????????? 。?? ,??????? FP1/HP ?? HP ????????(FP1/ceruloplasmin)?????????????????????? ,????????????? Fe2+?????????????????????[ 11] 。??????(cerulo-plasm , CP)??????????。?? Tf/TfR??? ,?????(lactoferrin , Lf)/LfR?????????(GPI)?? p97/??? p97????????????????????。?????????????????????????????????????[ 11] 。?? Tf/TfR???????????????? ,??? ,????????????????????? 、?????????? ,?????????[ 16 ,17] 。? 1　??????????　　(?)????????????　????????????? ,??????????????????????????? Tf ???? 。???????????????? 。???? ,??????????:Tf-Fe ?? Tf???(non-t ransferrin-bound iron ,NTBl)[ 11] 。???????·199·?????? 2002?? 33?? 3?????? , ????????? Tf-Fe????? ,?? NTBI 。????? Tf ???? Tf ??????????????。????? ,???30%? Tf ???????????[ 6 ,15] 。?????(CSF)??????????????? Tf???? Tf?????? ,??????? Tf ??。?? Tf???????????????? ,??????????????(??? Fe3+???)???? Tf??。????????????? Tf??????。????????????? ,?? NTBI。 NTBI ???????-Fe3+(?Fe2+)、????-Fe2+????-Fe2+(? Fe3+),?? Lf-Fe3+???? p97-Fe3+。?????????? Fe2+。Tf-Fe3+ 、Lf-Fe3+???? p97-Fe3+???? TfR 、LfR? GPI ?? p97??????????????。NTBI????? DMTl?????????(t rivalent cation-specif ic transporter ,TCT)??????????????????(?2)[ 11] 。?? ,?????[ 18 ～ 20]?? ,CP ??????????????????? ,???????????????。?????????? 。? 2　????????　　? 、?????????????(?)?????????????????????　????? ,??????????????????????????? 。??????????????????????? 。?????????? ,???????(NDs)????????? 。???????? NDs??(hallervor-den-spatz syndrome , HSS)、????(PD)、?????(AD)???????(HD)??????????? 。????????????????? ,??????????[ 11] 。?? ,????? ,?????????????????? ,???????????????:??????????????????????????????[ 11] 。?????? ,??????????????????????????????????????? ,??????????????????????????? 。1.????-??????-???????:????(???????)???????????????????????? 。???????????????。Curtis?[ 21]????????????????????????? , ?“??????” (Neuroferritinopathy)。??????·200· ?????? 2002?? 33?? 3??? HD? PD???????。???????????????????????? 。???????????(ferritin light polypeptide , FT L)???? 。??????????? FT L ???460 ～ 461??????????? ,?????????????? ,???????????????。???? 24?????(????)????? ,?????????? 。???????????? ,?? 1/3? 3/4??? 。“??????”??? ,?????????????????????????。??????????????? HSS ??? 。HSS ?????????????-1(Neurodegeneration w ith brain-i ron accumula-tion-1 , NBIA-1)?????????????(Pantothenate kinase associated neurodegeneration ,PKAN)。Zhou?[ 22]??????????????? 2(PANK2 , a novel panto thenate kinase gene)??(G411R)。??????? A ?????????? 。PANK2 ???????????? 。PANK2??????????????。??????????????????????????? ,????????? 。?????????? ,????? CP ????????[ 23] ,???????。CP ??????? CP ????????????????????? 。????????????????????????????????? CP ???? 。???? CP ??????????????。CP ???????????????????????????????????????????? 。?????????? ,??????? 2(iron regulatory pro tein 2 ,IRP2)???????????????????。LaVaute ?[ 24]?????? IRP2 ?????????????????????。 IRP2 ??????????????????????????????????。???????????IRP2 ????????????????????????。2.?????-????????-???????:?????? ,?????????????????????。?????????????????????????????。???????????????????????????????[ 2 , 11] 。???? ,?????????????????? 。??????????????????????。??????????????????????。???????? ,???? PD???? LfR? AD???? p97 ?????????[ 2] 。??????? LfR? p97????????????????? 。?????PD?????????? DMTl?????[ 12] 。???? ,?“??”?????????????????????????????????????? ,????????“??”????????? 。????????“??”?“??” ??????????????????????????? ,?????????????????????????????????????????[ 2 , 11] 。?? ,??????????????????????????? 。??????????? ,???????????????????????? 。??????????????????????。????????? ,???? IPR????? AD????????????? 。?????? AD ???? IRP/ IRE??????????? 。????? ???? TfR????????????? 。?? AD????????????????? ,?? AD??????。?? , ???????????-1(heme oxygenase-1 , HO-1)???????? AD 、PD??????????????????????????????????? 。HO-1??? 32kD?????(st ress pro-tein),??????????????? 、???????? 。???? HO-1 ??????? AD??????? 、?????????????????。?PD?? ,????????HO-1???????。?????????????????HO-1???????????????????????(Schipper.2000)。?????????????????????????????????? 2(stromal cell-derived receptor 2 , SDR2)。SDR2??????? b-561 ? Dcy tb ????。????????? , ???? SDR2 ?????????????????? 。?? ,??????????????????(Ponting.2001)。(?)???????????????????????????????　????????·201·?????? 2002?? 33?? 3???? ,????????????????????????。???????????????????????? ,?? Atox1(???????)??????????????(?????????????)????????????? 。??????????????????????????????。??????????????????????? 。?? ,?????????????? ,??????????????????????[ 11 , 25] ,????????????????????????????????????? 。?? ,?????????????????????????????[ 11] 。??????????? ,?????????????????? ,????????????? ,?????????????????????????。????? ,???????????????????????????????????????。? 、??????????????????????????????????????(? 3)。????????????????????????????(???????)??????(?? 、???????)??。?? ,?????????????????? 、?? 、?????????????。???????????????????????????? ,?????????????????????? 。?????? ,??????????????? ,?????????????????????????????????。?? ,???????????????????????。???? ,??????????????????????????? ,????????????????? 、????? 。????????? ,????????????Dcytb 、FP1? HP ??????? 。??????????????????? ??? ,???????????????????? ?????????????????? 。?????????????????????????????? ,???????????????????????????????????? 。???????????????????????????????????????? 。　　　　　　　? 3　?????????????????????????????? ? ? ?1　Qian ZM , Pu Y , Wang Q , et al.Iron Metabolism andCNS diseases(Chapter 17).I n ” Iron Metabolism - Funda-mental & Clinical Aspects” Ed.By Qian ZM , SciencePress , Beijing , 2000.329 ～ 352.2　Qian ZM , Wang Q.Expression of iron transpo rt proteinsand excessive iron accumulation in the brain in neurode-generative disorders.Brain Res Rev , 1998 , 27 257 ～ 267.3　Qian ZM , Xiao DS , Ke Y , et al.The increased nitric oxideis one of the causes fo r the changes in iron metabolism in theexercised rats.Am J Physiol , 2001 , 280 R739～ R743.4　Ho KP , Xiao DS , Ke Y , Qian ZM.The decreased activityof cytosolic aconitase in the liver , spleen and bone marrowin the exercised rats.Biochem Biophy s Res Comm , 2001 ,282 264 ～ 267.5　Qian ZM.Nitric ox ide and changes of iron metabo lism inexercise. Biolog ical Review , 2002 , DOI:10.1017/ S1464793102005997.·202· ?????? 2002?? 33?? 3?6　Qian ZM , Tang PL.Mechanisms of iron uptake by mam-malian cells.Biochem Biophy s Acta , 1995 , 1269 205 ～214.7　Qian ZM , Pu YM , Tang PL , et al.T ransferrin-bound ironuptake by the cultured cerebellar granule cells.NeurosciLett , 1998 , 251 9 ～ 12.8　Qian ZM , Pu YM , Ke Y , et al.Cerebellar granule cells ac-quire transferrin-free iron by a carrier-mediated process.Neuroscience, 1999 , 92 577～ 582.9　Qian ZM , To Y , Feng YM.Transferrin receptor on theplasma membrane of cultured rat astrocy tes.Exp BrainRes , 1999 , 129 473 ～ 476.10　Qian ZM , Liao QK , To Y , et al.T ransfer rin-bound andtransferrin-free iron uptake by the cultured brain astro-cy tes.Cell Mol Biol , 2000 , 46 541 ～ 548.11　Qian ZM , Shen X.Brain iron transpor t and neurode-generation.T rend Mol Med , 2001 , 7 103～ 108.12　Donovan A , Brownlie A , Zhou Y , et al.Positional cloningof zebrafish ferroportin 1 identifies a conserved ver tebrateiron expor ter.Nature , 2000 , 403 776 ～ 781.13　Vulpe CD , Kuo YM , Murphy TL , et al.Hephaestin , aceruloplasmin homologue implica ted in intestinal iron trans-po rt , is defective in the sla mouse.Nature Genet , 1999 ,21 195～ 199.14　McKie AT , Barrow D , Latunde-Dada GO , et al.An iron-regulated ferric reductase associated w ith the absorption ofdietary iron.Science , 2001 , 291 1755～ 1759.15　Qian ZM , Tang PL , Wang Q.Iron crosses the endosomalmembrane by a carrier-mediated process.P rog Biophy sMol Biol , 1997 , 67 1～ 15.16　Li HY , Sun HZ , Qian ZM.Drug delivery and targeting:Role of transferrin/ transferrin recepto r system. TrendPharmacol Sci , 2002 , 23 206～ 209.17　Li HY , Qian ZM.T ransferrin/ transfer rin receptor-medi-ated drug delivery.Med Res Rev , 2002 , 22 225 ～ 250.18　Qian ZM , Ke Y.Rethink the role of ceruloplasmin inbrain iron metabolism.Brain Res Rev , 2001 , 35 287 ～294.19　Qian ZM , Tsoi YK , Ke Y , et al.Ceruloplasmin promotesiron uptake rather than release in BT325 Cells.Exp BrainRes , 2001 , 140 369～ 374.20　Xie JX , Tsoi YK , Chang YZ , Ke Y , Qian ZM.Effects offerroxidase activity and species on ceruloplasmin mediated-iron uptake by BT325 Cells.Mol Brain Res , 2002 , 99 12～ 16.21　Cur tis ARJ , Fey C , Morris CM , et al.Mutation in thegene encoding ferritin light polypeptide causes dominantadult-onset basal gang lia disease.　Nature Gene t , 2001 ,28 350～ 354.22　Zhou B , Westaway SK , Levinson B , et al.A novel pan-tothenate kinase gene(PANK2)is defectiv e in Hallervor-den-Spatz syndrome.Na ture Genet , 2001 , 28 345 ～ 349.23　Yoshida K , Furihata K , Takeda S , et al.A mutation inthe ceruloplasmin gene is associated with systemichemosiderosis in humans.Nature Genet , 1995 , 9 267 ～272.24　LaVaute T , Smith S , Cooperman S , e t al.Targe ted dele-tion of the gene encoding iron regulatory protein-2 causesmisregulation o f iron metabolism and neurodegenerativedisease in mice.Nature Genet , 2001 , 27 209～ 214.25　Pu YM , Wang Q , Tang PL , Qian ZM.Effect of iron andlipid peroxidation on development of cerebellar granule cellin vitro.Neuroscience , 1999 , 89 855～ 861.?????????????????????????? 。???? ,??????????(???? 2.5μm ???)????? 、??????。??????????????????? ,?? 、?????????? 。?? ,???????Arden pope 、Geo rge Thurston? Daniel Krewski???????????????????? ,? 500 000???? 、??? 、????????? ,????? 、?? 、?? 、????? ,????????????? 10μg ,????????? 6%,???????? 8%。???????????? ,??????????????????? 15μg ,? 24???????65μg/m3 。(Science , 2002 , 295 1994)(朱晓松　邵　黎)·203·?????? 2002?? 33?? 3?

Brain iron metabolism and neurodegenerative diseases

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