多聚谷氨酰胺疾病候选致病基因THAP11功能的初步研究
|
摘要
多聚谷氨酰胺(polyglutamin,polyQ)疾病是一类由遗传因素导致的神经退行性疾病,该疾病是由于基因编码区域存在的CAG三核苷酸出现重复扩增,导致翻译产物中谷氨酰胺重复数目增加而引发,目前尚有大量类似的致病基因未被揭示。
死亡相关蛋白11(thanatos-associated protein-11,THAP11)是我们在研究与白血病发生密切相关的胚胎发育相关基因1(embryonic develop associated gene 1, EDAG-1)发现的与其存在相互作用的蛋白,属于THAP蛋白家族。基因的结构和多态性分析发现,THAP11序列中含有CAG编码片段,其分子中部的谷氨酰胺串联重复排列片段呈现高度的不稳定状态且易发生扩增,我们怀疑其可能为polyQ疾病的候选致病基因之一。为此,我们在前期实验筛查分析了正常人群和神经退行性病变患者的THAP11基因中CAG重复数,发现正常人群中广泛分布THAP11(29Q),而患者中多为THAP11(38Q),高表达THAP11能引起明显的细胞增殖抑制。初步确定THAP11可能为polyQ疾病的候选致病基因。
为进一步探讨THAP11的功能,本研究在PC12细胞中建立THAP11的蜕皮激素诱导表达系统,进一步研究THAP11的细胞生物学影响,同时为了后期在模式生物的水平上研究THAP11与polyQ疾病的相关性,我们还构建了一系列THAP11转基因线虫的载体,并制备了部分转基因线虫。结果发现THAP11(29Q)和THAP11(38Q)在PC12细胞中形成聚合物的时间和数目上存在差异。THAP11的表达能够导致PC12细胞产生G0/G1期阻滞,且随着THAP11的表达,PC12细胞的增殖受到抑制。机制探讨发现THAP11(29Q)及THAP11(38Q)均能减低细胞增殖中发挥重要作用的转录因子c-myc表达,但polyQ数目的增加并不能增强这种趋势。成功构建的THAP11转基因线虫表达载体,能够制备出转基因线虫,为后续进一步研究提供模型。
Polyglutamine(polyQ) diseases is a kind of neurodegenerative diseases caused by expanded CAG repeats in gene coding region resulting in translation products possessing expanded polyglutamine repeats. At present, a large number of pathogenic genes of polyQ diseases have not been revealed. THAP11 was the interact protein of EDAG1 when we study EDAG1, it belongs to THAP proteins family. The analysis of the construction and polymorphism of THAP11 found that it contains a section of polyglutamine fragment coded by CAG repeats which was very instable and essy to expand. Might THAP11 be a candidate gene for polyglutamine disorders? So, we screen the number of CAG repeats of THAP11 between nomal people and neurodegenerative diseases patients ,we found that THAP11(29Q) was common in the normal, and THAP11(38Q) was too much in the patients. The highly expressing of THAP11 can inhibit cell proliferation. we could primarily confirm THAP11 as a candidate gene for polyglutamine disorders.
For futher study of the function of THAP11, we have established the ecdysone-inducible expression system in PC12 cells,and try to research the cytobiology effect of it. In addition,for the reseach of the relationship between THAP11 and polyQ diseases on the level of model organism, we have constructed a series of the THAP11 transgenic Caenorhabditis elegans vectors and created some of the THAP11 transgenic Caenorhabditis elegans.
we have found that THAP11(29Q) and THAP11(38Q) was different in the time and nuber of the formation of protein aggregations in the PC12 cells. The expression of THAP11 can cause the arresting of cell cycle in G0/G1, with the expressing of THAP11, the PC12 cell proliferation can be inhibited. Investigating the mechanism of these effects we found that the expression of c-myc,which was important in cell proliferation, was decreased along with the expression of THAP11,but this effect was not associated with the number of polyQs. These THAP11 transgenic Caenorhabditis elegans vectors can be used to create transgenic Caenorhabditis elegans succefully.It can provide the model for the futher study.
死亡相关蛋白11(thanatos-associated protein-11,THAP11)是我们在研究与白血病发生密切相关的胚胎发育相关基因1(embryonic develop associated gene 1, EDAG-1)发现的与其存在相互作用的蛋白,属于THAP蛋白家族。基因的结构和多态性分析发现,THAP11序列中含有CAG编码片段,其分子中部的谷氨酰胺串联重复排列片段呈现高度的不稳定状态且易发生扩增,我们怀疑其可能为polyQ疾病的候选致病基因之一。为此,我们在前期实验筛查分析了正常人群和神经退行性病变患者的THAP11基因中CAG重复数,发现正常人群中广泛分布THAP11(29Q),而患者中多为THAP11(38Q),高表达THAP11能引起明显的细胞增殖抑制。初步确定THAP11可能为polyQ疾病的候选致病基因。
为进一步探讨THAP11的功能,本研究在PC12细胞中建立THAP11的蜕皮激素诱导表达系统,进一步研究THAP11的细胞生物学影响,同时为了后期在模式生物的水平上研究THAP11与polyQ疾病的相关性,我们还构建了一系列THAP11转基因线虫的载体,并制备了部分转基因线虫。结果发现THAP11(29Q)和THAP11(38Q)在PC12细胞中形成聚合物的时间和数目上存在差异。THAP11的表达能够导致PC12细胞产生G0/G1期阻滞,且随着THAP11的表达,PC12细胞的增殖受到抑制。机制探讨发现THAP11(29Q)及THAP11(38Q)均能减低细胞增殖中发挥重要作用的转录因子c-myc表达,但polyQ数目的增加并不能增强这种趋势。成功构建的THAP11转基因线虫表达载体,能够制备出转基因线虫,为后续进一步研究提供模型。
Polyglutamine(polyQ) diseases is a kind of neurodegenerative diseases caused by expanded CAG repeats in gene coding region resulting in translation products possessing expanded polyglutamine repeats. At present, a large number of pathogenic genes of polyQ diseases have not been revealed. THAP11 was the interact protein of EDAG1 when we study EDAG1, it belongs to THAP proteins family. The analysis of the construction and polymorphism of THAP11 found that it contains a section of polyglutamine fragment coded by CAG repeats which was very instable and essy to expand. Might THAP11 be a candidate gene for polyglutamine disorders? So, we screen the number of CAG repeats of THAP11 between nomal people and neurodegenerative diseases patients ,we found that THAP11(29Q) was common in the normal, and THAP11(38Q) was too much in the patients. The highly expressing of THAP11 can inhibit cell proliferation. we could primarily confirm THAP11 as a candidate gene for polyglutamine disorders.
For futher study of the function of THAP11, we have established the ecdysone-inducible expression system in PC12 cells,and try to research the cytobiology effect of it. In addition,for the reseach of the relationship between THAP11 and polyQ diseases on the level of model organism, we have constructed a series of the THAP11 transgenic Caenorhabditis elegans vectors and created some of the THAP11 transgenic Caenorhabditis elegans.
we have found that THAP11(29Q) and THAP11(38Q) was different in the time and nuber of the formation of protein aggregations in the PC12 cells. The expression of THAP11 can cause the arresting of cell cycle in G0/G1, with the expressing of THAP11, the PC12 cell proliferation can be inhibited. Investigating the mechanism of these effects we found that the expression of c-myc,which was important in cell proliferation, was decreased along with the expression of THAP11,but this effect was not associated with the number of polyQs. These THAP11 transgenic Caenorhabditis elegans vectors can be used to create transgenic Caenorhabditis elegans succefully.It can provide the model for the futher study.
引文
1. Zhu CY, Li CY, Li Y,et al. Cell growth suppression by thanatos-associated protein 11(THAP11) is mediated by transcriptional downregulation of c-Myc.Cell Death Differ. 2009 Mar;16(3):395-405. Epub 2008 Nov 14.
2. Vincent JB, Paterson AD, Strong E, et al. The unstable trinucleotide repeat story of major psychosis. Am J Med Genet. 2000 Spring;97(1):77-97.
3. Hearne CM, Todd JA. Trinucleotide repeat polymorphism at the CRYG1 locus. Nucleic Acids Res. 1991 Oct 11;19(19):5450.
4. Nakahori Y, Knight SJ, et al. Molecular heterogeneity of the fragile X syndrome. Nucleic Acids Res. 1991 Aug 25;19(16):4355-9.
5. Jiang H, Tang B, Xia K, et al. Spinocerebellar ataxia type 6 in Mainland China: molecular and clinical features in four families. J Neurol Sci. 2005 Sep 15;236(1-2):25-9.
6. Xie QY, Liang XL, Li XH, et al. Molecular genetics and its clinical application in the diagnosis of spinocerebellar ataxias. Zhonghua Yi Xue Yi Chuan Xue Za Zhi. 2005 Feb;22(1):71-3. Chinese.
7. Brusco A, Gellera C, Cagnoli C, et al. Molecular genetics of hereditary spinocerebellar ataxia: mutation analysis of spinocerebellar ataxia genes and CAG/CTG repeat expansion detection in 225 Italian families. Arch Neurol. 2004 May;61(5):727-33.
8. Baba Y, Uitti RJ, Farrer MJ, et al. Sporadic SCA8 mutation resembling corticobasal degeneration. Parkinsonism Relat Disord. 2005 May;11(3):147-50.
9. Paulson HL, Perez MK, Trottier Y, et al.Intranuclear inclusions of expanded polyglutamine protein in spinocerebellar ataxia type 3. Neuron. 1997 Aug;19(2):333-44.
10. Koeppen AH. The pathogenesis of spinocerebellar ataxia. Cerebellum. 2005;4(1):62-73.
11. Wood JD, Beaujeux TP, Shaw PJ. Protein aggregation in motor neurone disorders.Neuropathol Appl Neurobiol. 2003 Dec;29(6):529-45.
12. DiFiglia M, Sapp E, Chase KO, et al. Aggregation of huntingtin in neuronal intranuclear inclusions and dystrophic neurites in brain. Science. 1997 Sep 26;277(5334):1990-3.
13. Rolfs A, Koeppen AH, Bauer I, et al. Clinical features and neuropathology of autosomal dominant spinocerebellar ataxia (SCA17). Ann Neurol. 2003 Sep;54(3):367-75.
14. Peter W. Faber, Janet R, et al. Polyglutamine-mediated dysfunction and apoptotic death of a Caenorhabditis elegans sensory neuron. PNAS, Jan 1999; 96: 179 - 184.6.
15. Wang H, Lim PJ, Karbowski M, et al. Effects of overexpression of huntingtin proteins on mitochondrial integrity. Hum Mol Genet. 2009 Feb 15;18(4):737-52.
16. Beal MF. Mitochondria take center stage in aging and neurodegeneration.Ann Neurol. 2005 Oct;58(4):495-505.
17. The Huntingtun’s Disease Collaborative Research Group. A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington's disease chromosomes. Cell. 1993 Mar 26;72(6):817-8.
18. Howard RA, Sharma P, Hajjar C, et al. Ubiquitin conjugating enzymes participate in polyglutamine protein aggregation. BMC Cell Biol. 2007 Jul 30;8:32.
19. Voisine C, Varma H, Walker N,et al. Identification of potential therapeutic drugs for huntington's disease using Caenorhabditis elegans. PLoS ONE. 2007 Jun 6;2(6):e504.
20. Ratovitski T, Nakamura M, D'Ambola J, et al. N-terminal proteolysis of full-length mutant huntingtin in an inducible PC12 cell model of Huntington's disease. Cell Cycle. 2007 Dec 1;6(23):2970-81.
21. Wang H, Monteiro MJ. Ubiquilin interacts and enhances the degradation of expanded-polyglutamine proteins.Biochem Biophys Res Commun. 2007 Aug 24;360(2):423-7. Epub 2007 Jun 25.
22. Wang H, Monteiro MJ. Ubiquilin overexpression reduces GFP-polyalanine-induced protein aggregates and toxicity.Exp Cell Res. 2007 Aug 1;313(13):2810-20. Epub 2007 Apr 6.
23. Bowman AB, Yoo SY, Dantuma NP, et al. Neuronal dysfunction in a polyglutamine disease model occurs in the absence of ubiquitin-proteasome system impairment and inversely correlates with the degree of nuclear inclusion formation. Hum Mol Genet. 2005 Mar 1;14(5):679-91. Epub 2005 Jan 20.
24. Wang H, Lim PJ, Yin C, et al. Suppression of polyglutamine-induced toxicity in cell and animal models of Huntington's disease by ubiquilin. Hum Mol Genet. 2006 Mar 15;15(6):1025-41. Epub 2006 Feb 6.
25. Hideki Sakahira, Peter Breuer, Manajit K, et al. Molecular chaperones as modulators of polyglutamine protein aggregation and toxicity. PNAS.Dec 2002 99: 16412 - 16418.
26. Yamada M, Sato T, Tsuji S, et al. CAG repeat disorder models and human neuropathology: similarities and differences. Acta Neuropathol. 2008 Jan;115(1):71-86. Epub 2007 Sep 5.
27. Roussigne M, Cayrol C, Clouaire T, et al. THAP1 is a nuclear proapoptotic factor that links prostate-apoptosis-response-4 (Par-4) to PML nuclear bodies. Oncogene, 2002;22(16): 2432-42.
28. Macfarlan T, Kutney S, Altman B, et al. Human THAP7 is a chromatin-associated histone tail-binding protein that represses transcription via recruitment of HDAC3 and nuclear hormone receptor corepressor. J Biol Chem, 2005; 280(8): 7346-58.
29. Macfarlan T, Parker JB, Nagata K, et al. Thanatos-associated protein 7 associates with template activating factor-Ibeta and inhibits histone acetylation to repress transcription. Mol Endocrinol, 2006;20(2): 335-47.
30. Bowman AB, Yoo SY, Dantuma NP, Zoghbi HY. Neuronal dysfunction in a polyglutamine disease model occurs in the absence of ubiquitin-proteasome system impairment and inversely correlates with the degree of nuclear inclusion formation. Hum Mol Genet. 2005 Mar 1;14(5):679-91. Epub 2005 Jan.
31.秦正红,顾振纶,林芳.亨廷顿舞蹈病的分子病理研究进展.中国药理学通报,2004;20(4):378-82.
32. Jacobson S, Pillus L. Modifing chromatin and concepts of cancer. Curr Opin Genet Dev,1999;9(2):175-84.
33. Ye Q, Hu YF, Zhong H, et al. BRCA1-induced large-scale chromatin unfolding and allele-specific effects of cancer-predisposing mutations. J Cell Biol,2001;155(6):911-21. Heather R, Brignull, James F, et al. The Stress of Misfolded Proteins C. elegans Models for Neurodegenerative Disease and Aging. Adv Exp Med Biol. 2007;594:167-8.
34. Brignull HR, Morley JF, Garcia SM, et al. Modeling Polyglutamine Pathogenesis in C. elegans Methods Enzymol. 2006;412:256-82.
35. Brignull HR, Moore FE, Tang SJ, et al. Polyglutamine proteins at the pathogenic threshold display neuron-specific aggregation in a pan-neuronal Caenorhabditis elegans model. J Neurosci. 2006 Jul 19;26(29):7597-606.
36. James F. Morley, Heather R,et al. The threshold for polyglutamine-expansion protein aggregation and cellular toxicity is dynamic and influenced by aging in Caenorhabditis elegans. PNAS, Aug 2002; 99: 10417-10422.
1. The Huntington's Disease Collaborative Research Group. A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington's disease chromosomes. Cell 1993;72:971-983.
2. Zoghbi, H.Y. & Orr, H.T. Glutamine repeats and neurodegeneration. Annu. Rev. Neurosci 2000; 23: 217-247
3. Paulson HL, Fischbeck KH. Trinucleotide repeats in neurogenetic disorders. Annu Rev Neurosci. 1996;19:79-107.
4. Suhr, S.T., Senut, M.C., Whitelegge, J.P., Faull, K.F., Cuizon, D.B. and Gage, F.H. Identities of sequestered proteins in aggregates from cells with induced polyglutamine expression. J. Cell. Biol., 2001; 153, 283–294.
5. Moulder K.L., Onodera O, Burke, J.R, et al. Generation of neuronal intranuclear inclusions bypolyglutamine-GFP: analysis of inclusion clearance and toxicity as a function of polyglutamine length. J. Neurosci., 1999; 19, 705–715.
6. Gutekunst C.A, Li S.H, Yi H, et al . Nuclear and neuropil aggregates in Huntington’s disease: relationship to neuropathology. J. Neurosci.,1999;19, 2522–2534.
7. Evert BO, Wullner U, Klockgether T. Cell death in polyglutamine diseases. Cell Tissue Res,2000 Jul;301(1):189-204.
8. 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 SCA-1 mice. Neuron 1999; 24:879-892.
9. Stephen W Daviesa, Kathryn Beardsalla, Mark Turmainea, et al. Are neuronal intranuclear inclusions the common neuropathology of triplet-repeat disorders with polyglutamine-repeat expansions? The Lancet(1998), 351:131-133.
10. Chen M, Ona VO, Li M et al. Minocycline inhibits caspase-1 and caspase-3 expression and delays mortality in a transgenic mouse model of Huntington’s disease. Nat Med 2000; 6: 797-801.
11. Lipinski M.M, Yuan J. Mechanisms of cell death in polyglutamine expansion diseases. Curr. Opin. Pharmaco 2004 . 4:85-90.
12. Cummings CJ, Mancini MA, Antalffy B, et al. Chaperone suppression of aggre- gation and altered subcellular proteasome localization imply protein misfolding in SCA1. Nat Genet 1998; 19: 148-154.
13. 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(4):673-682.
14. Yvert G, Lindenberg KS, et al. Expanded polyglutamines induce neurodegeneration and trans-neuronal alterations in cerebellum and retina of SCA7 transgenic mice. Hum Mol Genet. 2000; 9(17): 2491-2506.
15. Violante V, Luongo A, Pepe I, et al . Transglutaminase-dependent formation of protein aggregates as possible biochemical mechanism for polygluta- mine diseases. Brain Res Bull 2001; 56: 169-172.
16. Mastroberardion PG, Iannicola C, Nardacci R, et al.‘Tissue’trans-glutaminase ablation reduces neuronal death and prolongs survival in a mouse model of Hunting- ton’s disease. Cell Death Differ 2002; 9:873-880.
17. Frederick C. Nucifora Jr., Masayuki Sasaki, Matthew F. Peters, et al. Interference by Huntingtin and Atrophin-1 with CBP-Mediated transcription leading to cellular toxicity. Science 2001; 291: 2423-2428.
18. Theo Mantamadiotis1, Thomas Lemberger, Susanne C, et al. Disruption of CREB function in brain leads to neurodegeneration. Nat Genet.2002 31:47-54.
19. Starikov EB, Lehrach H, Wanker EE. Folding of oligoglutamines: a theoretical approach based upon thermodynamics and molecular mechanics. J Biomol Struct Dyn. 1999; 17(3):409-27.
20. Scherzinger E, Lurz R. Huntingtin-encoded polyglutamine expansion form amyloid-like protein aggregates in vitro and in vivo. Cell 1997; 90:549-558.
21. H. Quesneville , D. Nouaud , D. Anxolabehere. Recurrent Recruitment of the THAP DNA-Binding Domain and Molecular Domestication of the P Transposable Element. Mol Bio Evol. 2005; 22(3):741-746.
22. Kumar A, Yang Y, Flati V, et al. Deficient cytokine signaling in mouse embro fibroblasts with a targeted deletion in the PKR gene: role of IRF-1 and NF-Kb. EMBO J. 1997; 16: 406-413.
23. Roussigne M, Cayrol C, Clouaire T, et al. THAP1 is a nuclear proapoptotic factor that links prostate-apoptosis-response-4(Par-4) to PML nuclear bodies. Oncogene. 2003, 22: 2432-2442.
24. Todd Macfarlan, Sara Kutney, Brian Altman, et al. Human THAP7 is a chromatin associated, histone tail binding protein that represses transcription via recruitment of HDAC3 and NCoR J Biol Chem. 2005;280(8):7346-7358.
25. Goldberg YP et al. Molecular analysis of new mutations for Huntington's disease: intermediate alleles and sex of origin effects. Nat Genet 1993; 5:174-179.
26. Monoi H, Futaki S, Kugimiya S, et al. Poly-L-glutamine forms cation channels: relevance to the pathogenesis of the polyglutamine diseases. Biophys J. 2000 ; 78(6):2892-2899.
27. Flanigan K, Gardner K, Alderson K, et al. Autosomal dominant spinocerebellar ataxia with sen sory axonal neuropathy (SCA4): clinical description and genetic localization to chromosome 16q22.1. Am J Hum Genet 1996 ;59: 392–399.
28. Hellenbroich Y, Bubel S, Pawlack H, et al. Refinement of the spinocerebellar ataxia type 4 locus in a large German family and exclusion of CAG repeat expansions in this region. J Neurol 2003; 250:668–671.
29. Li M, Ishikawa K, Toru S, Tomimitsu H, et al. Physical map and haplotype analysis of 16q- -linked autosomal dominant cerebellar ataxia (ADCA) type III in Japan. J Hum Genet, 2003; 48: 111–118.
30. Koide, R. et al., Unstable expansion of CAG repeat in hereditary dentatorubral-pallidoluysian atrophy (DRPLA). Nature Genetics 1994; 6:9-13.
31. Kawaguchi Y, et al. CAG expansions in a novel gene for Machado- Joseph disease at chromosome 14q32.1. Nature Genetics, 1994; 8: 221-227.
32. Tait D, Riccio M, Sittler A, et al. Ataxin-3 is transported into the nucleus and associates with the nuclear matrix. Hum Mol Genet 1998; 7: 991-997.
33. Kaytor MD, Duvick LA, Skinner pj, et al. Nuclear localization of the spinocerebellar ataxia type 7 protein, ataxin-7. Hum Mol Genet. 1999; 8: 1657-1664.
34. Trottier Y, Lutz Y, Stevanin G, et al. Polyglutamine expansion as a pathological epitope in Huntington’s disease and four dominant cerebellar ataxias. Nature 1995; 378: 403-406.
35. Everett C.M, Wood N.W. Trinucleotide repeats and neurodegenerative disease. Brain 2004, 127 :2385-2405.
36. McCampbell A, Taylor JP, Taye AA, et al. CREB-binding protein sequestration by expanded polygultamine. Hum Mol Genet 2000; 9: 2197-2202.
37. Shimohata T, Nakajima T, Yamada M, et al. Expanded polyglutamine stretches interact with TAFⅡ130, interfering with CREB-dependent transcription. Nat Genet 2000; 26: 29-36.
38. Voisine C, Varma H, Walker N,et al. Identification of potential therapeutic drugs for huntington's disease using Caenorhabditis elegans. PLoS ONE. 2007 Jun6;2(6):e504.
39. Weissmann C,Brandt R. Mechanisms of neurodegenerative diseases: insights from live cell imaging.J Neurosci Res. 2008 Feb 15;86(3):504-11.
40. Wang H, Monteiro MJ. Ubiquilin interacts and enhances the degradation of expanded-polyglutamine proteins.Biochem Biophys Res Commun. 2007 Aug 24;360(2):423-7. Epub 2007 Jun 25.
41. Brignull HR, Moore FE, Tang SJ, et al. Polyglutamine proteins at the pathogenic threshold display neuron-specific aggregation in a pan-neuronal Caenorhabditis elegans model. J Neurosci. 2006 Jul 19;26(29):7597-606.
42. Peter W. Faber, Janet R, et al. Polyglutamine-mediated dysfunction and apoptotic death of a Caenorhabditis elegans sensory neuron. PNAS, Jan 1999; 96: 179 - 184.
43. James F. Morley, Heather R,et al. The threshold for polyglutamine-expansion protein aggregation and cellular toxicity is dynamic and influenced by aging in Caenorhabditis elegans. PNAS, Aug 2002; 99: 10417 - 10422.
44. 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.
45. Wang H, Monteiro MJ. Ubiquilin overexpression reduces GFP-polyalanine-induced protein aggregates and toxicity.Exp Cell Res. 2007 Aug 1;313(13):2810-20.
46. Mastroberardion PG, Iannicola C, Nardacci R, et al.‘Tissue’trans-glutaminase ablation reduces neuronal death and prolongs survival in a mouse model of Hunting- ton’s disease. Cell Death Differ 2002; 9:873-880.
47. Frederick C. Nucifora Jr., Masayuki Sasaki, et al. Interference by Huntingtin and Atrophin-1 with CBP-Mediated transcription leading to cellular toxicity. Science 2001; 291: 2423-2428.
48. Theo Mantamadiotis, Thomas Lemberger, Susanne C, et al. Disruption of CREB function in brain leads to neurodegeneration. Nat Genet.2002 31:47-54.
49. Starikov EB, Lehrach H, Wanker EE. Folding of oligoglutamines: a theoretical approach based upon thermodynamics and molecular mechanics. J Biomol Struct Dyn. 1999; 17(3):409-27.
50. Scherzinger E, Lurz R. Huntingtin-encoded polyglutamine expansion form amyloid-like protein aggregates in vitro and in vivo. Cell 1997; 90:549-558.
2. Vincent JB, Paterson AD, Strong E, et al. The unstable trinucleotide repeat story of major psychosis. Am J Med Genet. 2000 Spring;97(1):77-97.
3. Hearne CM, Todd JA. Trinucleotide repeat polymorphism at the CRYG1 locus. Nucleic Acids Res. 1991 Oct 11;19(19):5450.
4. Nakahori Y, Knight SJ, et al. Molecular heterogeneity of the fragile X syndrome. Nucleic Acids Res. 1991 Aug 25;19(16):4355-9.
5. Jiang H, Tang B, Xia K, et al. Spinocerebellar ataxia type 6 in Mainland China: molecular and clinical features in four families. J Neurol Sci. 2005 Sep 15;236(1-2):25-9.
6. Xie QY, Liang XL, Li XH, et al. Molecular genetics and its clinical application in the diagnosis of spinocerebellar ataxias. Zhonghua Yi Xue Yi Chuan Xue Za Zhi. 2005 Feb;22(1):71-3. Chinese.
7. Brusco A, Gellera C, Cagnoli C, et al. Molecular genetics of hereditary spinocerebellar ataxia: mutation analysis of spinocerebellar ataxia genes and CAG/CTG repeat expansion detection in 225 Italian families. Arch Neurol. 2004 May;61(5):727-33.
8. Baba Y, Uitti RJ, Farrer MJ, et al. Sporadic SCA8 mutation resembling corticobasal degeneration. Parkinsonism Relat Disord. 2005 May;11(3):147-50.
9. Paulson HL, Perez MK, Trottier Y, et al.Intranuclear inclusions of expanded polyglutamine protein in spinocerebellar ataxia type 3. Neuron. 1997 Aug;19(2):333-44.
10. Koeppen AH. The pathogenesis of spinocerebellar ataxia. Cerebellum. 2005;4(1):62-73.
11. Wood JD, Beaujeux TP, Shaw PJ. Protein aggregation in motor neurone disorders.Neuropathol Appl Neurobiol. 2003 Dec;29(6):529-45.
12. DiFiglia M, Sapp E, Chase KO, et al. Aggregation of huntingtin in neuronal intranuclear inclusions and dystrophic neurites in brain. Science. 1997 Sep 26;277(5334):1990-3.
13. Rolfs A, Koeppen AH, Bauer I, et al. Clinical features and neuropathology of autosomal dominant spinocerebellar ataxia (SCA17). Ann Neurol. 2003 Sep;54(3):367-75.
14. Peter W. Faber, Janet R, et al. Polyglutamine-mediated dysfunction and apoptotic death of a Caenorhabditis elegans sensory neuron. PNAS, Jan 1999; 96: 179 - 184.6.
15. Wang H, Lim PJ, Karbowski M, et al. Effects of overexpression of huntingtin proteins on mitochondrial integrity. Hum Mol Genet. 2009 Feb 15;18(4):737-52.
16. Beal MF. Mitochondria take center stage in aging and neurodegeneration.Ann Neurol. 2005 Oct;58(4):495-505.
17. The Huntingtun’s Disease Collaborative Research Group. A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington's disease chromosomes. Cell. 1993 Mar 26;72(6):817-8.
18. Howard RA, Sharma P, Hajjar C, et al. Ubiquitin conjugating enzymes participate in polyglutamine protein aggregation. BMC Cell Biol. 2007 Jul 30;8:32.
19. Voisine C, Varma H, Walker N,et al. Identification of potential therapeutic drugs for huntington's disease using Caenorhabditis elegans. PLoS ONE. 2007 Jun 6;2(6):e504.
20. Ratovitski T, Nakamura M, D'Ambola J, et al. N-terminal proteolysis of full-length mutant huntingtin in an inducible PC12 cell model of Huntington's disease. Cell Cycle. 2007 Dec 1;6(23):2970-81.
21. Wang H, Monteiro MJ. Ubiquilin interacts and enhances the degradation of expanded-polyglutamine proteins.Biochem Biophys Res Commun. 2007 Aug 24;360(2):423-7. Epub 2007 Jun 25.
22. Wang H, Monteiro MJ. Ubiquilin overexpression reduces GFP-polyalanine-induced protein aggregates and toxicity.Exp Cell Res. 2007 Aug 1;313(13):2810-20. Epub 2007 Apr 6.
23. Bowman AB, Yoo SY, Dantuma NP, et al. Neuronal dysfunction in a polyglutamine disease model occurs in the absence of ubiquitin-proteasome system impairment and inversely correlates with the degree of nuclear inclusion formation. Hum Mol Genet. 2005 Mar 1;14(5):679-91. Epub 2005 Jan 20.
24. Wang H, Lim PJ, Yin C, et al. Suppression of polyglutamine-induced toxicity in cell and animal models of Huntington's disease by ubiquilin. Hum Mol Genet. 2006 Mar 15;15(6):1025-41. Epub 2006 Feb 6.
25. Hideki Sakahira, Peter Breuer, Manajit K, et al. Molecular chaperones as modulators of polyglutamine protein aggregation and toxicity. PNAS.Dec 2002 99: 16412 - 16418.
26. Yamada M, Sato T, Tsuji S, et al. CAG repeat disorder models and human neuropathology: similarities and differences. Acta Neuropathol. 2008 Jan;115(1):71-86. Epub 2007 Sep 5.
27. Roussigne M, Cayrol C, Clouaire T, et al. THAP1 is a nuclear proapoptotic factor that links prostate-apoptosis-response-4 (Par-4) to PML nuclear bodies. Oncogene, 2002;22(16): 2432-42.
28. Macfarlan T, Kutney S, Altman B, et al. Human THAP7 is a chromatin-associated histone tail-binding protein that represses transcription via recruitment of HDAC3 and nuclear hormone receptor corepressor. J Biol Chem, 2005; 280(8): 7346-58.
29. Macfarlan T, Parker JB, Nagata K, et al. Thanatos-associated protein 7 associates with template activating factor-Ibeta and inhibits histone acetylation to repress transcription. Mol Endocrinol, 2006;20(2): 335-47.
30. Bowman AB, Yoo SY, Dantuma NP, Zoghbi HY. Neuronal dysfunction in a polyglutamine disease model occurs in the absence of ubiquitin-proteasome system impairment and inversely correlates with the degree of nuclear inclusion formation. Hum Mol Genet. 2005 Mar 1;14(5):679-91. Epub 2005 Jan.
31.秦正红,顾振纶,林芳.亨廷顿舞蹈病的分子病理研究进展.中国药理学通报,2004;20(4):378-82.
32. Jacobson S, Pillus L. Modifing chromatin and concepts of cancer. Curr Opin Genet Dev,1999;9(2):175-84.
33. Ye Q, Hu YF, Zhong H, et al. BRCA1-induced large-scale chromatin unfolding and allele-specific effects of cancer-predisposing mutations. J Cell Biol,2001;155(6):911-21. Heather R, Brignull, James F, et al. The Stress of Misfolded Proteins C. elegans Models for Neurodegenerative Disease and Aging. Adv Exp Med Biol. 2007;594:167-8.
34. Brignull HR, Morley JF, Garcia SM, et al. Modeling Polyglutamine Pathogenesis in C. elegans Methods Enzymol. 2006;412:256-82.
35. Brignull HR, Moore FE, Tang SJ, et al. Polyglutamine proteins at the pathogenic threshold display neuron-specific aggregation in a pan-neuronal Caenorhabditis elegans model. J Neurosci. 2006 Jul 19;26(29):7597-606.
36. James F. Morley, Heather R,et al. The threshold for polyglutamine-expansion protein aggregation and cellular toxicity is dynamic and influenced by aging in Caenorhabditis elegans. PNAS, Aug 2002; 99: 10417-10422.
1. The Huntington's Disease Collaborative Research Group. A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington's disease chromosomes. Cell 1993;72:971-983.
2. Zoghbi, H.Y. & Orr, H.T. Glutamine repeats and neurodegeneration. Annu. Rev. Neurosci 2000; 23: 217-247
3. Paulson HL, Fischbeck KH. Trinucleotide repeats in neurogenetic disorders. Annu Rev Neurosci. 1996;19:79-107.
4. Suhr, S.T., Senut, M.C., Whitelegge, J.P., Faull, K.F., Cuizon, D.B. and Gage, F.H. Identities of sequestered proteins in aggregates from cells with induced polyglutamine expression. J. Cell. Biol., 2001; 153, 283–294.
5. Moulder K.L., Onodera O, Burke, J.R, et al. Generation of neuronal intranuclear inclusions bypolyglutamine-GFP: analysis of inclusion clearance and toxicity as a function of polyglutamine length. J. Neurosci., 1999; 19, 705–715.
6. Gutekunst C.A, Li S.H, Yi H, et al . Nuclear and neuropil aggregates in Huntington’s disease: relationship to neuropathology. J. Neurosci.,1999;19, 2522–2534.
7. Evert BO, Wullner U, Klockgether T. Cell death in polyglutamine diseases. Cell Tissue Res,2000 Jul;301(1):189-204.
8. 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 SCA-1 mice. Neuron 1999; 24:879-892.
9. Stephen W Daviesa, Kathryn Beardsalla, Mark Turmainea, et al. Are neuronal intranuclear inclusions the common neuropathology of triplet-repeat disorders with polyglutamine-repeat expansions? The Lancet(1998), 351:131-133.
10. Chen M, Ona VO, Li M et al. Minocycline inhibits caspase-1 and caspase-3 expression and delays mortality in a transgenic mouse model of Huntington’s disease. Nat Med 2000; 6: 797-801.
11. Lipinski M.M, Yuan J. Mechanisms of cell death in polyglutamine expansion diseases. Curr. Opin. Pharmaco 2004 . 4:85-90.
12. Cummings CJ, Mancini MA, Antalffy B, et al. Chaperone suppression of aggre- gation and altered subcellular proteasome localization imply protein misfolding in SCA1. Nat Genet 1998; 19: 148-154.
13. 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(4):673-682.
14. Yvert G, Lindenberg KS, et al. Expanded polyglutamines induce neurodegeneration and trans-neuronal alterations in cerebellum and retina of SCA7 transgenic mice. Hum Mol Genet. 2000; 9(17): 2491-2506.
15. Violante V, Luongo A, Pepe I, et al . Transglutaminase-dependent formation of protein aggregates as possible biochemical mechanism for polygluta- mine diseases. Brain Res Bull 2001; 56: 169-172.
16. Mastroberardion PG, Iannicola C, Nardacci R, et al.‘Tissue’trans-glutaminase ablation reduces neuronal death and prolongs survival in a mouse model of Hunting- ton’s disease. Cell Death Differ 2002; 9:873-880.
17. Frederick C. Nucifora Jr., Masayuki Sasaki, Matthew F. Peters, et al. Interference by Huntingtin and Atrophin-1 with CBP-Mediated transcription leading to cellular toxicity. Science 2001; 291: 2423-2428.
18. Theo Mantamadiotis1, Thomas Lemberger, Susanne C, et al. Disruption of CREB function in brain leads to neurodegeneration. Nat Genet.2002 31:47-54.
19. Starikov EB, Lehrach H, Wanker EE. Folding of oligoglutamines: a theoretical approach based upon thermodynamics and molecular mechanics. J Biomol Struct Dyn. 1999; 17(3):409-27.
20. Scherzinger E, Lurz R. Huntingtin-encoded polyglutamine expansion form amyloid-like protein aggregates in vitro and in vivo. Cell 1997; 90:549-558.
21. H. Quesneville , D. Nouaud , D. Anxolabehere. Recurrent Recruitment of the THAP DNA-Binding Domain and Molecular Domestication of the P Transposable Element. Mol Bio Evol. 2005; 22(3):741-746.
22. Kumar A, Yang Y, Flati V, et al. Deficient cytokine signaling in mouse embro fibroblasts with a targeted deletion in the PKR gene: role of IRF-1 and NF-Kb. EMBO J. 1997; 16: 406-413.
23. Roussigne M, Cayrol C, Clouaire T, et al. THAP1 is a nuclear proapoptotic factor that links prostate-apoptosis-response-4(Par-4) to PML nuclear bodies. Oncogene. 2003, 22: 2432-2442.
24. Todd Macfarlan, Sara Kutney, Brian Altman, et al. Human THAP7 is a chromatin associated, histone tail binding protein that represses transcription via recruitment of HDAC3 and NCoR J Biol Chem. 2005;280(8):7346-7358.
25. Goldberg YP et al. Molecular analysis of new mutations for Huntington's disease: intermediate alleles and sex of origin effects. Nat Genet 1993; 5:174-179.
26. Monoi H, Futaki S, Kugimiya S, et al. Poly-L-glutamine forms cation channels: relevance to the pathogenesis of the polyglutamine diseases. Biophys J. 2000 ; 78(6):2892-2899.
27. Flanigan K, Gardner K, Alderson K, et al. Autosomal dominant spinocerebellar ataxia with sen sory axonal neuropathy (SCA4): clinical description and genetic localization to chromosome 16q22.1. Am J Hum Genet 1996 ;59: 392–399.
28. Hellenbroich Y, Bubel S, Pawlack H, et al. Refinement of the spinocerebellar ataxia type 4 locus in a large German family and exclusion of CAG repeat expansions in this region. J Neurol 2003; 250:668–671.
29. Li M, Ishikawa K, Toru S, Tomimitsu H, et al. Physical map and haplotype analysis of 16q- -linked autosomal dominant cerebellar ataxia (ADCA) type III in Japan. J Hum Genet, 2003; 48: 111–118.
30. Koide, R. et al., Unstable expansion of CAG repeat in hereditary dentatorubral-pallidoluysian atrophy (DRPLA). Nature Genetics 1994; 6:9-13.
31. Kawaguchi Y, et al. CAG expansions in a novel gene for Machado- Joseph disease at chromosome 14q32.1. Nature Genetics, 1994; 8: 221-227.
32. Tait D, Riccio M, Sittler A, et al. Ataxin-3 is transported into the nucleus and associates with the nuclear matrix. Hum Mol Genet 1998; 7: 991-997.
33. Kaytor MD, Duvick LA, Skinner pj, et al. Nuclear localization of the spinocerebellar ataxia type 7 protein, ataxin-7. Hum Mol Genet. 1999; 8: 1657-1664.
34. Trottier Y, Lutz Y, Stevanin G, et al. Polyglutamine expansion as a pathological epitope in Huntington’s disease and four dominant cerebellar ataxias. Nature 1995; 378: 403-406.
35. Everett C.M, Wood N.W. Trinucleotide repeats and neurodegenerative disease. Brain 2004, 127 :2385-2405.
36. McCampbell A, Taylor JP, Taye AA, et al. CREB-binding protein sequestration by expanded polygultamine. Hum Mol Genet 2000; 9: 2197-2202.
37. Shimohata T, Nakajima T, Yamada M, et al. Expanded polyglutamine stretches interact with TAFⅡ130, interfering with CREB-dependent transcription. Nat Genet 2000; 26: 29-36.
38. Voisine C, Varma H, Walker N,et al. Identification of potential therapeutic drugs for huntington's disease using Caenorhabditis elegans. PLoS ONE. 2007 Jun6;2(6):e504.
39. Weissmann C,Brandt R. Mechanisms of neurodegenerative diseases: insights from live cell imaging.J Neurosci Res. 2008 Feb 15;86(3):504-11.
40. Wang H, Monteiro MJ. Ubiquilin interacts and enhances the degradation of expanded-polyglutamine proteins.Biochem Biophys Res Commun. 2007 Aug 24;360(2):423-7. Epub 2007 Jun 25.
41. Brignull HR, Moore FE, Tang SJ, et al. Polyglutamine proteins at the pathogenic threshold display neuron-specific aggregation in a pan-neuronal Caenorhabditis elegans model. J Neurosci. 2006 Jul 19;26(29):7597-606.
42. Peter W. Faber, Janet R, et al. Polyglutamine-mediated dysfunction and apoptotic death of a Caenorhabditis elegans sensory neuron. PNAS, Jan 1999; 96: 179 - 184.
43. James F. Morley, Heather R,et al. The threshold for polyglutamine-expansion protein aggregation and cellular toxicity is dynamic and influenced by aging in Caenorhabditis elegans. PNAS, Aug 2002; 99: 10417 - 10422.
44. 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.
45. Wang H, Monteiro MJ. Ubiquilin overexpression reduces GFP-polyalanine-induced protein aggregates and toxicity.Exp Cell Res. 2007 Aug 1;313(13):2810-20.
46. Mastroberardion PG, Iannicola C, Nardacci R, et al.‘Tissue’trans-glutaminase ablation reduces neuronal death and prolongs survival in a mouse model of Hunting- ton’s disease. Cell Death Differ 2002; 9:873-880.
47. Frederick C. Nucifora Jr., Masayuki Sasaki, et al. Interference by Huntingtin and Atrophin-1 with CBP-Mediated transcription leading to cellular toxicity. Science 2001; 291: 2423-2428.
48. Theo Mantamadiotis, Thomas Lemberger, Susanne C, et al. Disruption of CREB function in brain leads to neurodegeneration. Nat Genet.2002 31:47-54.
49. Starikov EB, Lehrach H, Wanker EE. Folding of oligoglutamines: a theoretical approach based upon thermodynamics and molecular mechanics. J Biomol Struct Dyn. 1999; 17(3):409-27.
50. Scherzinger E, Lurz R. Huntingtin-encoded polyglutamine expansion form amyloid-like protein aggregates in vitro and in vivo. Cell 1997; 90:549-558.