亨廷顿病模型进展及展望
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摘要
亨廷顿病(Huntington’s disease,HD)是一种典型的神经退行性疾病。该病是由单基因HTT突变导致的遗传性疾病,当CAG重复序列>36时发病,HD患者出现变异蛋白的累积和神经元死亡病理特征,伴随着行为、认知、精神方面的障碍。其清晰的病因使得HD成为研究神经退行性疾病的首选模式疾病。本文将对现有HD动物模型取得的成果进行简单综述,以期为此类神经退行性疾病的研究提供思路。
Huntington's disease(HD)is a typical hereditary neurodegenerative disease caused by single HTT gene mutation,and a CAG repeat of >36 in the HTT gene may lead to HD. HD patients are characterized by the accumulation of variant proteins and neuronal death,with behavioral,cognitive,and mental disorders. Clear etiology makes HD an ideal model for the analysis of neurodegenerative diseases. This article briefly reviews the achievements in animal models of HD,in order to provide ideas for the research on such neurodegenerative diseases.
Huntington's disease(HD)is a typical hereditary neurodegenerative disease caused by single HTT gene mutation,and a CAG repeat of >36 in the HTT gene may lead to HD. HD patients are characterized by the accumulation of variant proteins and neuronal death,with behavioral,cognitive,and mental disorders. Clear etiology makes HD an ideal model for the analysis of neurodegenerative diseases. This article briefly reviews the achievements in animal models of HD,in order to provide ideas for the research on such neurodegenerative diseases.
引文
[1]Gusella JF,MacDonald ME,Ambrose CM,et al.Molecular genetics of Huntington’s disease[J].Archives of neurology,1993,50(11):1157-1163.
[2]Vonsattel JP,Myers RH,Stevens TJ,et al.Neuropathological classification of Huntington’s disease[J].Journal of Neuropathology&Experimental Neurology,1985,44(6):559-577.
[3]Ross CA,Aylward EH,Wild EJ,et al.Huntington disease:natural history,biomarkers and prospects for therapeutics[J].Nature Reviews Neurology,2014,10(4):204-216.
[4]Bates GP,Dorsey R,Gusella JF,et al.Huntington disease[J].Nature Reviews Disease Primers,2015,1:15005.
[5]Rüb U,Seidel K,Heinsen H,et al.Huntington’s disease(HD):the neuropathology of a multisystem neurodegenerative disorder of the human brain[J].Brain Pathology,2016,26(6):726-740.
[6]Quigley J.Juvenile Huntington’s disease:diagnostic and treatment considerations for the psychiatrist[J].Current Psychiatry Reports,2017,19(2):9.
[7]Silva A,de Almeida AV,Macedo-Ribeiro S.Polyglutamine expansion diseases:more than simple repeats[J].Journal of Structural Biology,2018,201(2):139-154.
[8]Weiss KR,Kimura Y,Lee WC,et al.Huntingtin aggregation kinetics and their pathological role in a Drosophila Huntington’s disease model[J].Genetics,2012,190(4):581-600.
[9]Das S,Rajanikant GK.Huntington disease:Can a zebrafish trail leave more than a ripple?[J].Neuroscience&Biobehavioral Reviews,2014,45:258-261.
[10]Karlovich CA,John RM,Ramirez L,et al.Characterization of the Huntington’s disease(HD)gene homologue in the zebrafish Danio rerio[J].Gene,1998,217(1-2):117-125.
[11]Mangiarini L,Sathasivam K,Seller M,et al.Exon 1 of the HDgene with an expanded CAG repeat is sufficient to cause a progressive neurological phenotype in transgenic mice[J].Cell,1996,87(3):493-506.
[12]Ravikumar B,Vacher C,Berger Z,et al.Inhibition of m TOR induces autophagy and reduces toxicity of polyglutamine expansions in fly and mouse models of Huntington disease[J].Nat Genet,2004,36(6):585-595.
[13]Jin J,Albertz J,Guo Z,et al.Neuroprotective effects of PPAR-agonist rosiglitazone in N171-82Q mouse model of Huntington’s disease[J].Journal of Neurochemistry,2013,125(3):410-419.
[14]Gil-Mohapel JM.Screening of therapeutic strategies for Huntington’s disease in YAC128 transgenic mice[J].CNS Neuroscience&Therapeutics,2012,18(1):77-86.
[15]Asa H,Chunni Z,Aroa RG,et al.Deuterium-reinforced linoleic acid lowers lipid peroxidation and mitigates cognitive impairment in the Q140 knock in mouse model of Huntington’s disease[J].The FEBS Journal,2018[Epub ahead of print].DOI:10.1111/febs.14590.
[16]Wheeler VC,White JK,Gutekunst CA,et al.Long glutamine tracts cause nuclear localization of a novel form of huntingtin in medium spiny striatal neurons in Hdh Q92 and HdhQ111 knock-in mice[J].Hum Mol Genet,2000,9(4):503-513.
[17]Menalled LB,Sison JD,Wu Y,et al.Early motor dysfunction and striosomal distribution of huntingtin microaggregates in Huntington’s disease knock-in mice[J].J Neurosci,2002,22(18):8266-8276.
[18]Woodman B,Butler R,Landles C,et al.The Hdh(Q150/Q150)knock-in mouse model of HD and the R6/2 exon 1 model develop comparable and widespread molecular phenotypes[J].Brain Res Bull,2007,72(2-3):83-97.
[19]Mattson MP.Apoptosis in neurodegenerative disorders[J].Nat Rev Mol Cell Biol,2000,1(2):120-129.
[20]Yuan J,Yankner BA.Apoptosis in the nervous system[J].Nature,2000,407(6805):802-809.
[21]Reid SJ,Patassini S,Renée R Handley,et al.Further molecular characterisation of the OVT73 transgenic sheep model of Huntington’s disease identifies cortical aggregates[J].Journal of Huntington’s Disease,2013,2(3):279-295.
[22]Handley RR,Reid SJ,Brauning R,et al.Brain urea increase is an early Huntington’s disease pathogenic event observed in a prodromal transgenic sheep model and HD cases[J].Proc Natl Acad Sci USA,2017,114(52):E11293-11302.
[23]Handley RR,Reid SJ,Patassini S,et al.Metabolic disruption identified in the Huntington’s disease transgenic sheep model[J].Sci Rep,2016,6(1):20681.
[24]Jacobsen JC,Bawden CS,Rudiger SR,et al.An ovine transgenic Huntington’s disease model[J].Hum Mol Genet,2010,19(10):1873-1882.
[25]Yang SH,Cheng PH,Banta H,et al.Towards a transgenic model of Huntington’s disease in a non-human Primate[J].Nature,2008,453(7197):921-924.
[26]Yu ZX,Li SH,Evans J,et al.Mutant Huntingtin causes contextdependent neurodegeneration in mice with Huntington’s disease[J].JNeurosci,2003,23(6):2193-2202.
[27]Yang D,Wang CE,Zhao B,et al.Expression of Huntington’s disease protein results in apoptotic neurons in the brains of cloned transgenic pigs[J].Hum Mol Genet,2010,19(20):3983-3994.
[28]Yan S,Tu Z,Liu Z,et al.A Huntingtin knockin pig model recapitulates features of selective neurodegeneration in Huntington’s disease[J].Cell,2018,173(4):989-1002.
[29]Wild EJ,Tabrizi SJ.Therapies targeting DNA and RNA in Huntington’s disease[J].Lancet Neurol,2017,16(10):837-847.
[30]Lin L,Jin Z,Tan H,et al.Atypical ubiquitination by E3 ligase WWP1 inhibits the proteasome-mediated degradation of mutant Huntingtin[J].Brain Research,2016,1643:103-112.
[31]Luo H,Cao L,Liang X,et al.Herp promotes degradation of mutant Huntingtin:involvement of the proteasome and molecular chaperones[J].Molecular Neurobiology,2018,55(10):7652-7668.
[32]Carmo C,Naia L,Lopes C,et al.Mitochondrial dysfunction in Huntington’s disease[J].Polyglutamine Disorders,2018,1049:59-83.
[33]Jin J,Albertz J,Guo Z,et al.Neuroprotective effects of PPAR-agonist rosiglitazone in N171-82Q mouse model of Huntington’s disease[J].Journal of Neurochemistry,2013,125(3):410-419.
[34]Duyao MP,Auerbach AB,Ryan A,et al.Inactivation of the mouse Huntington’s disease gene homolog Hdh[J].Science,1995,269(5222):407-410.
[35]Nasir J,Floresco SB,O’Kusky JR,et al.Targeted disruption of the Huntington’s disease gene results in embryonic lethality and behavioral and morphological changes in heterozygotes[J].Cell,1995,81(5):811-823.
[36]Zeitlin S,Liu JP,Chapman DL,et al.Increased apoptosis and early embryonic lethality in mice nullizygous for the Huntington’s disease gene homologue[J].Nat Genet,1995,11(2):155-163.
[37]MacDonald ME,Duyao M,Calzonetti T,et al.Targeted inactivation of the mouse Huntington’s disease gene homolog Hdh[J].Cold Spring Harb Symp Quant Biol,1996,61:627-638.
[38]Wang G,Liu X,Gaertig MA,et al.Ablation of huntingtin in adult neurons is nondeleterious but its depletion in young mice causes acute pancreatitis[J].Proc Natl Acad Sci U S A,2016,113(12):3359-3364.
[39]Boudreau RL,McBride JL,Martins I,et al.Nonallele-specific silencing of mutant and wild-type huntingtin demonstrates therapeutic efficacy in Huntington’s disease mice[J].Mol Ther,2009,17(6):1053-1063.
[40]Drouet V,Perrin V,Hassig R,et al.Sustained effects of nonallelespecific Huntingtin silencing[J].Ann Neurol,2009,65(3):276-285.
[41]Grondin R,Kaytor MD,Ai Y,et al.Six-month partial suppression of Huntingtin is well tolerated in the adult rhesus striatum[J].Brain,2012,135(Pt4):1197-1209.
[42]Yang S,Chang R,Yang H,et al.CRISPR/Cas9-mediated gene editing ameliorates neurotoxicity in mouse model of Huntington’s disease[J].J Clin Invest,2017,127(7):2719-2724.
[2]Vonsattel JP,Myers RH,Stevens TJ,et al.Neuropathological classification of Huntington’s disease[J].Journal of Neuropathology&Experimental Neurology,1985,44(6):559-577.
[3]Ross CA,Aylward EH,Wild EJ,et al.Huntington disease:natural history,biomarkers and prospects for therapeutics[J].Nature Reviews Neurology,2014,10(4):204-216.
[4]Bates GP,Dorsey R,Gusella JF,et al.Huntington disease[J].Nature Reviews Disease Primers,2015,1:15005.
[5]Rüb U,Seidel K,Heinsen H,et al.Huntington’s disease(HD):the neuropathology of a multisystem neurodegenerative disorder of the human brain[J].Brain Pathology,2016,26(6):726-740.
[6]Quigley J.Juvenile Huntington’s disease:diagnostic and treatment considerations for the psychiatrist[J].Current Psychiatry Reports,2017,19(2):9.
[7]Silva A,de Almeida AV,Macedo-Ribeiro S.Polyglutamine expansion diseases:more than simple repeats[J].Journal of Structural Biology,2018,201(2):139-154.
[8]Weiss KR,Kimura Y,Lee WC,et al.Huntingtin aggregation kinetics and their pathological role in a Drosophila Huntington’s disease model[J].Genetics,2012,190(4):581-600.
[9]Das S,Rajanikant GK.Huntington disease:Can a zebrafish trail leave more than a ripple?[J].Neuroscience&Biobehavioral Reviews,2014,45:258-261.
[10]Karlovich CA,John RM,Ramirez L,et al.Characterization of the Huntington’s disease(HD)gene homologue in the zebrafish Danio rerio[J].Gene,1998,217(1-2):117-125.
[11]Mangiarini L,Sathasivam K,Seller M,et al.Exon 1 of the HDgene with an expanded CAG repeat is sufficient to cause a progressive neurological phenotype in transgenic mice[J].Cell,1996,87(3):493-506.
[12]Ravikumar B,Vacher C,Berger Z,et al.Inhibition of m TOR induces autophagy and reduces toxicity of polyglutamine expansions in fly and mouse models of Huntington disease[J].Nat Genet,2004,36(6):585-595.
[13]Jin J,Albertz J,Guo Z,et al.Neuroprotective effects of PPAR-agonist rosiglitazone in N171-82Q mouse model of Huntington’s disease[J].Journal of Neurochemistry,2013,125(3):410-419.
[14]Gil-Mohapel JM.Screening of therapeutic strategies for Huntington’s disease in YAC128 transgenic mice[J].CNS Neuroscience&Therapeutics,2012,18(1):77-86.
[15]Asa H,Chunni Z,Aroa RG,et al.Deuterium-reinforced linoleic acid lowers lipid peroxidation and mitigates cognitive impairment in the Q140 knock in mouse model of Huntington’s disease[J].The FEBS Journal,2018[Epub ahead of print].DOI:10.1111/febs.14590.
[16]Wheeler VC,White JK,Gutekunst CA,et al.Long glutamine tracts cause nuclear localization of a novel form of huntingtin in medium spiny striatal neurons in Hdh Q92 and HdhQ111 knock-in mice[J].Hum Mol Genet,2000,9(4):503-513.
[17]Menalled LB,Sison JD,Wu Y,et al.Early motor dysfunction and striosomal distribution of huntingtin microaggregates in Huntington’s disease knock-in mice[J].J Neurosci,2002,22(18):8266-8276.
[18]Woodman B,Butler R,Landles C,et al.The Hdh(Q150/Q150)knock-in mouse model of HD and the R6/2 exon 1 model develop comparable and widespread molecular phenotypes[J].Brain Res Bull,2007,72(2-3):83-97.
[19]Mattson MP.Apoptosis in neurodegenerative disorders[J].Nat Rev Mol Cell Biol,2000,1(2):120-129.
[20]Yuan J,Yankner BA.Apoptosis in the nervous system[J].Nature,2000,407(6805):802-809.
[21]Reid SJ,Patassini S,Renée R Handley,et al.Further molecular characterisation of the OVT73 transgenic sheep model of Huntington’s disease identifies cortical aggregates[J].Journal of Huntington’s Disease,2013,2(3):279-295.
[22]Handley RR,Reid SJ,Brauning R,et al.Brain urea increase is an early Huntington’s disease pathogenic event observed in a prodromal transgenic sheep model and HD cases[J].Proc Natl Acad Sci USA,2017,114(52):E11293-11302.
[23]Handley RR,Reid SJ,Patassini S,et al.Metabolic disruption identified in the Huntington’s disease transgenic sheep model[J].Sci Rep,2016,6(1):20681.
[24]Jacobsen JC,Bawden CS,Rudiger SR,et al.An ovine transgenic Huntington’s disease model[J].Hum Mol Genet,2010,19(10):1873-1882.
[25]Yang SH,Cheng PH,Banta H,et al.Towards a transgenic model of Huntington’s disease in a non-human Primate[J].Nature,2008,453(7197):921-924.
[26]Yu ZX,Li SH,Evans J,et al.Mutant Huntingtin causes contextdependent neurodegeneration in mice with Huntington’s disease[J].JNeurosci,2003,23(6):2193-2202.
[27]Yang D,Wang CE,Zhao B,et al.Expression of Huntington’s disease protein results in apoptotic neurons in the brains of cloned transgenic pigs[J].Hum Mol Genet,2010,19(20):3983-3994.
[28]Yan S,Tu Z,Liu Z,et al.A Huntingtin knockin pig model recapitulates features of selective neurodegeneration in Huntington’s disease[J].Cell,2018,173(4):989-1002.
[29]Wild EJ,Tabrizi SJ.Therapies targeting DNA and RNA in Huntington’s disease[J].Lancet Neurol,2017,16(10):837-847.
[30]Lin L,Jin Z,Tan H,et al.Atypical ubiquitination by E3 ligase WWP1 inhibits the proteasome-mediated degradation of mutant Huntingtin[J].Brain Research,2016,1643:103-112.
[31]Luo H,Cao L,Liang X,et al.Herp promotes degradation of mutant Huntingtin:involvement of the proteasome and molecular chaperones[J].Molecular Neurobiology,2018,55(10):7652-7668.
[32]Carmo C,Naia L,Lopes C,et al.Mitochondrial dysfunction in Huntington’s disease[J].Polyglutamine Disorders,2018,1049:59-83.
[33]Jin J,Albertz J,Guo Z,et al.Neuroprotective effects of PPAR-agonist rosiglitazone in N171-82Q mouse model of Huntington’s disease[J].Journal of Neurochemistry,2013,125(3):410-419.
[34]Duyao MP,Auerbach AB,Ryan A,et al.Inactivation of the mouse Huntington’s disease gene homolog Hdh[J].Science,1995,269(5222):407-410.
[35]Nasir J,Floresco SB,O’Kusky JR,et al.Targeted disruption of the Huntington’s disease gene results in embryonic lethality and behavioral and morphological changes in heterozygotes[J].Cell,1995,81(5):811-823.
[36]Zeitlin S,Liu JP,Chapman DL,et al.Increased apoptosis and early embryonic lethality in mice nullizygous for the Huntington’s disease gene homologue[J].Nat Genet,1995,11(2):155-163.
[37]MacDonald ME,Duyao M,Calzonetti T,et al.Targeted inactivation of the mouse Huntington’s disease gene homolog Hdh[J].Cold Spring Harb Symp Quant Biol,1996,61:627-638.
[38]Wang G,Liu X,Gaertig MA,et al.Ablation of huntingtin in adult neurons is nondeleterious but its depletion in young mice causes acute pancreatitis[J].Proc Natl Acad Sci U S A,2016,113(12):3359-3364.
[39]Boudreau RL,McBride JL,Martins I,et al.Nonallele-specific silencing of mutant and wild-type huntingtin demonstrates therapeutic efficacy in Huntington’s disease mice[J].Mol Ther,2009,17(6):1053-1063.
[40]Drouet V,Perrin V,Hassig R,et al.Sustained effects of nonallelespecific Huntingtin silencing[J].Ann Neurol,2009,65(3):276-285.
[41]Grondin R,Kaytor MD,Ai Y,et al.Six-month partial suppression of Huntingtin is well tolerated in the adult rhesus striatum[J].Brain,2012,135(Pt4):1197-1209.
[42]Yang S,Chang R,Yang H,et al.CRISPR/Cas9-mediated gene editing ameliorates neurotoxicity in mouse model of Huntington’s disease[J].J Clin Invest,2017,127(7):2719-2724.
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