摘要
背景：
遗传性脊髓小脑型共济失调(hereditary spinocerebellar ataxia, SCAs)是一类常见的神经系统遗传病,根据neuromuscualr website (http://neuromuscular.wustl.edu/ataxia/domatax.html)截止到2009年11月5日发布的信息,迄今至少已定位了30种基因型,其中18个疾病基因已被克隆。脊髓小脑型共济失调3型(spinocerebellar ataxia type 3/Machado-Joseph disease,SCA3/MJD)为最常见的SCAs亚型,在中国人群中几乎占常染色体显性遗传脊髓小脑型共济失调的60%,其致病基因-MJD1基因编码区的3’端含有一段CAG三核苷酸重复序列,正常人重复次数约12-40次,而SCA3/MJD患者可达52-86次,且CAG异常重复次数越多,发病年龄越早,症状越严重。
迄今为止已发现九种神经退行性疾病是由于致病基因开放阅读框(open reading frame, ORF)中CAG三核苷酸重复扩展突变所致,包括SCA1、SCA2、SCA3/MJD、SCA6、SCA7、SCA17,以及亨廷顿舞蹈病(huntington disease,HD)、脊髓延髓肌萎缩症(spinal and bulbar muscular atrophy, SBMA)、齿状核红核苍白球路易体萎缩症(dentatorubral-pallidoluysian atrophy, DRPLA)。该类疾病统称为多聚谷氨酰胺(polyglutamine, polyQ)疾病。目前有关polyQ疾病的发病机制尚未完全阐明,临床上亦缺乏有效的治疗。
组蛋白乙酰化是一种翻译后修饰,能导致染色质结构及转录调控的改变。目前认为组蛋白乙酰化与去乙酰化水平在组蛋白乙酰转移酶(histone acetyltransferase,HAT)和组蛋白去乙酰化酶(histone deacetylase,HDAC)的作用下保持着动态平衡,从而维持基因正常的转录调控功能。有研究表明组蛋白乙酰化水平降低可能是引起细胞毒性作用、促发polyQ疾病转录异常的关键步骤。国内外不少学者已经在体外证实组蛋白去乙酰化酶抑制剂(histone deacetylase inhibitors, HDACIs)能够抑制polyQ蛋白的毒性作用,缓解HD、SBMA、DRPLA等的病情,延缓疾病进展。然而对于同样属于polyQ病的SCA3/MJD疾病,至今国内外尚未见有关运用HDACIs进行治疗的相关研究报道。
Hv(因涉及到保密性问题,本实验研究中所运用的组蛋白去乙酰化酶抑制剂统一用“Hv”表示)属于HDACIs中的短链脂肪酸类,其半衰期长,毒副作用小,已在临床上用于治疗其他疾病多年。Hv除了通过抑制组蛋白去乙酰化而调节基因转录外,还可通过多条途径,如通过诱导热休克蛋白(heat shock protein, HSP)的表达来保护神经元等。而在前期工作中,本课题组成员已证实HSP22对SCA3/MJD转基因果蝇模型具有保护作用,因此我们选用HDACIs中的Hv来进行SCA3/MJD的治疗研究。目的：
探讨Hv对SCA3/MJD细胞模型及转基因果蝇模型的保护作用及其机制,为临床上运用HDACIs治疗SCA3/MJD疾病提供科学的理论依据。
方法：
1.应用荧光显微镜技术了解Hv对SCA3/MJD细胞模型中异常蛋白聚集体的影响。
2.运用Western-blot技术检测Hv对野生型、含polyQ扩展突变型ataxin-3蛋白及乙酰化组蛋白H3和H4表达水平的影响。
3.应用PI/Annexin-V-FITC双染流式细胞仪技术分析Hv对SCA3/MJD细胞模型凋亡率的影响。
4.利用GAL4/UAS系统构建在眼睛及神经系统表达致病蛋白的SCA3/MJD转基因果蝇模型。
5.利用光学显微镜和扫描电镜观察Hv对SCA3/MJD转基因果蝇模型复眼的影响。
6.通过表型观察,了解Hv对SCA3/MJD转基因果蝇模型爬行能力及寿命的影响。结果：
1.野生型ataxin-3蛋白在细胞中呈弥散分布,而polyQ扩展突变型ataxin-3蛋白能在细胞中形成异常蛋白聚集体；不同剂量Hv干预后,polyQ扩展突变型SCA3/MJD细胞模型中异常蛋白聚集体阳性细胞率及polyQ扩展突变型ataxin-3蛋白的表达水平较其未给Hv干预对照组相比无明显变化。
2.PI/Annexin V-FITC双染流式细胞仪结果显示：未予以Hv干预的空载体pEGFP-N1转染组及野生型pEGFP-N1-ataxin-3-20Q转染组细胞早期凋亡率无明显差异,而pEGFP-N1-ataxin-3-68Q转染组细胞的早期凋亡率明显高于空载体组及野生型组细胞；不同剂量的Hv干预polyQ扩展突变型SCA3/MJD细胞模型后,其早期细胞凋亡率明显下降,且剂量越大凋亡率下降越明显。
3.Western-blot检测发现：未予以Hv干预的空载体pEGFP-N1转染组及野生型pEGFP-N1-ataxin-3-20Q转染组细胞中乙酰化组蛋白H3、H4表达水平无明显差别,而polyQ扩展突变型SCA3/MJD细胞模型中乙酰化组蛋白H3、H4表达水平低于空载体组和野生型组。不同剂量Hv干预后,随着Hv剂量的增加,polyQ扩展突变型SCA3/MJD细胞模型的乙酰化组蛋白H3、H4表达水平逐渐升高。
4.利用GAL4/UAS系统分别构建了在果蝇眼睛和神经系统中以不同水平表达MJDtr-Q78蛋白的SCA3/MJD转基因果蝇模型。该模型表现为进行性的复眼结果破坏、色素脱失,爬行能力下降及寿命缩短,且其严重程度与MJDtr-Q78蛋白的表达量及表达部位有关。
5.Hv干预SCA3/MJD转基因果蝇模型后,其复眼结构破坏及色素脱失好转,且Hv剂量越大,复眼改善越明显。
6.Hv干预SCA3/MJD转基因果蝇模型后,其爬行能力得到一定程度的改善,且Hv剂量为1.0mM到1.5mM时爬行能力改善最明显。
7.一定剂量的Hv (0.5mM)能延长SCA3/MJD转基因果蝇模型的寿命,而当Hv剂量过大时反而会缩短SCA3/MJD转基因果蝇模型及野生型果蝇的寿命。
结论：
1.进一步证实polyQ扩展突变能导致细胞内异常蛋白聚集体的形成,发现Hv不能减少SCA3/MJD细胞模型中异常蛋白聚集体的形成和ataxin-3蛋白的表达。
2.进一步证实polyQ扩展突变能诱导细胞凋亡,发现Hv可抑制polyQ扩展突变型ataxin-3蛋白的细胞毒性作用,从而降低SCA3/MJD细胞的早期凋亡率。
3.发现SCA3/MJD细胞模型中存在组蛋白H3、H4乙酰化水平的降低,而Hv可提高SCA3/MJD细胞模型的组蛋白H3、H4乙酰化水平。
4.成功地构建了在果蝇眼睛和神经系统中以不同水平表达MJDtr-Q78蛋白的SCA3/MJD转基因果蝇模型,进一步证实扩展突变型polyQ蛋白的表达量及表达部位与SCA3/MJD转基因果蝇模型的表型及严重程度存在相关性。
5.发现一定剂量的Hv能减轻SCA3/MJD转基因果蝇模型的复眼结构破坏与色素脱失,并能改善SCA3/MJD转基因果蝇模型的爬行能力和延长其寿命。即一定剂量的Hv在一定程度上具有保护SCA3/MJD转基因果蝇模型的作用。
Background:
The hereditary spinocerebellar ataxias(SCAs) are a heterogeneous group of neurodegenerative disorders.To date, at least 30 gene loci responsible for SCAs have been mapped, in which 18 pathogenic genes have been cloned. Among them, spinocerebellar ataxia type 3/Machado-Joseph disease (SCA3/MJD) is the most common subtype, which accounts for almost 60% SCAs in China. SCA3/MJD disease is an autosomal dominant neurodegenerative disorder caused by CAG trinucleotide repeat expansion within the coding region of MJDl gene (also called ataxin-3 gene).Normal MJD1 contains 12-40 glutamines near the C-terminus, and polyglutamine tract expands to 52-86 glutamines in disease-causing mutant MJDl.
So far nine disorders have been found to be caused by CAG trinucleotide repeat expanded mutation within the open reading frame (ORF) of pathogenic gene, including SCA1,SCA2,SCA3/MJD, SCA6, SCA7,SCA17,huntington disease (HD),spinal-bulbar muscular atrophy (SBMA) and dentatorubral-pallidoluysian atrophy (DRPLA).Such diseases are referred to polyglutamine (polyQ) diseases.Up to now, the pathomechanism of polyQ diseases have not been fully explained. It is generally hypothesized that deregulation of transcription is a key contributor to the pathogenesis of DRPLA, HD and other polyQ diseases. However there are currently no known cure or effective treatment for these diseases.
As a post-translational modification, the acetylation and deacetylation of histones are modulated by the interplay between histone acetyltransferase (HAT) and histone deacetylase (HDAC),which results in modification to chromatin structure and regulation of transcription. It is generally thought that HAT activity leads to an increase in gene transcription through the opening of chromatin architecture by adding acetyl groups.Conversely, HDAC removes acetyl group, which leads to gene repression through chromatin condensation. Studies in numerous have shown that aberrant activity of histone deacetylases or histone acetyltransferase might be an underlying mechanism of transcriptional dysregulation in polyQ diseases.It suggests that the balance of histone acetylation is a good target for therapeutic intervention of this kind of diseases.Consistent with this idea, numerous studies have shown a therapeutic role for HDAC inhibitors (HDACIs) such as sodium butyrate (SB),TSA, suberoylanilide hydroxamic acid(SAHA) and so on, as candidate drugs for the treatment of HD,DRPLA and SBMA.However, the effects of HDACIs on models of SCA3/MJD disease have never been tested.
Hv (due to confidentiality issues,"Hv" reprensents the HDACIs we used in the study) is one of the HDACIs and belongs to short-chain fatty acids.It has been used clinically in other diseases for many years.In addition to inhibit histone acetylation and regulation of gene transcription, Hv can also play an important role in protecting neurons by a number of ways, such as inducing the express of heat shock protein (HSP).We have confirmed that expression of HSP22 protects the SCA3/MJD from neurodegeneration on Drosophila models. Based on these points, here we selected Hv to investigate the therapeutic effects of HDACIs in SCA3/MJD disease.
Objective:
To further investigate the mechanism of SCA3/MJD disease and examine the therapeutic potential of Hv in SCA3/MJD cells and transgenic Drosophila models.
Methods:
1.Fluorescence technique was utilized to study the effect of Hv on the formation of abnormal aggregate by polyglutamine expanded ataxin-3.
2.Western-blot were undertaken to study the effect of Hv on the expression level of polyglutamine expanded ataxin-3 protein, acetyl-histone H3 and acetyl-histone H4 protein in SCA3/MJD cell model.
3.Flow cytometry of PI/Annexin-V-FITC was used to study the effect of Hv on the apoptosis of wild-type and polyglutamine expanded ataxin-3.
4.SCA3/MJD transgenic Drosophila models were constructed by GAL4/UAS system.
5.Light microscope and scanning electron microscope(SEM) were used to observing the effect of Hv on the eye morphology of SCA3/MJD transgenic Drosophila models.
6.Observing the effect of Hv on the climbing ability and lifespan of SCA3/MJD transgenic Drosophila models.
Results:
1.Using GFP fluorescence technique, we found that ataxin-3-20Q distributed scattered and ataxin-3-68Q aggregated in nucleus or cytoplasm. We analyzed the quantitation of abnormal aggregations in polyglutamine expanded ataxin-3 group without or with different doses of Hv intervention, but found no significantly difference (P>0.05).By western-blot, we also found no difference on the expression level of polyglutamine expanded ataxin-3 protein between Hv intervention group and controls.
2.The result of flow cytometry showed the early apoptosis rate of pEGFP-N1-ataxin-3-68Q transfected cells was significantly higher than the empty pEGFP-N1 transfected group and pEGFP-N1-ataxin-3-20Q transfected group (P<0.05).After Hv intervention, the early apoptosis rate of pEGFP-N1-ataxin-3-68Q transfected cells was significantly decreased, and the greater the dose, the lower the apoptosis rate.
3.The empty pEGFP-N1 vector transfected cells and pEGFP-N1-ataxin-3-20Q transfected cells had the same expression level of acetyl-histone H3 and acetyl-histone H4 protein, but the pEGFP-N1-ataxin-3-68Q transfected cells(SCA3/MJD cell model) had lower. After the intervention of different dosage of Hv, the expression level of acetyl-histone H3 protein of pEGFP-N1-ataxin-3-68Q transfected cells was gradually increased.
4.Using GAL4/UAS transformation system, SCA3/MJD transgenic Drosophila models were constructed by gmr-GAL4 and elav-GAL4 which drive target selective gene expression in developing eyes and neurons, respectively. In no case did expression of MJDtr-Q27 protein have a phenotypic effect.But expression of MJDtr-Q78 protein caused progressive loss of pigmentation and collapse of the eye, decreasing of climbing ability and shortening of lifespan. The severity of the phenotype was relavant to the expression level and site of MJDtr-Q78 protein.
5.As for SCA3/MJD transgenic Drosophila models,the loss of pigmentation and collapse of the eye was mitigated by feeding Hv.
6.The climbing ability of SCA3/MJD transgenic Drosophila models was improved by feeding Hv.Especially, 1.OmM or 1.5mM Hv could obviously improve it's climbing ability.
7.We found that proper dosage of Hv (0.5mM) could extend the SCA3/MJD transgenic Drosophila lifespan. However too much Hv would shorten the lifespan of both SCA3/MJD transgenic Drosophila and wild-type Drosophila.
Conclusion:
1.For the first time, we find that Hv can not prevent the abnormal protein aggregation, or the expression level of polyglutamine expanded ataxin-3 protein in SCA3/MJD cell model.
2.We further confirm that polyglutamine expansion mutation can induce apoptosis, and for the first time we find that Hv can inhibit the cytotoxicity of polyglutamine expanded ataxin-3 protein, thereby reduce the early apoptosis rate of SCA3/MJD cell model.
3.For the first time, we find that Hv can increase the expression level of acetyl-histone H3 and acetyl-histone H4 protein which have been decresed because polyglutamine expanded ataxin-3 mutation in SCA3/MJD cell model.
4.We successfully constructed SCA3/MJD transgenic Drosophila models which selective express human MJDtr-Q78 protein with different levels in developing eyes or neurons respectively. We further confirm that the expression level and site of polyglutamine expanded ataxin-3 (MJDtr-Q78)protein are concerned to the severity of SCA3/MJD symptoms.
5.For the first time, we find that proper dosage of Hv has therapeutic potential in SCA3/MJD transgenic Drosophila models by reducing pigment loss and structural damage of eyes, improving climbing ability and extending lifespan.
引文
[1]Schols L, Amoiridis G, Buttner T, et al.Autosomal dominant cerebellar ataxia: phenotypic differences in genetically defined subtypes? Ann Neurol,1997, 42(6):924-32.
[2]Tang B, Liu C, Shen L, et al. Frequency of SCA1,SCA2, SCA3/MJD, SCA6, SCA7, and DRPLA CAG trinucleotide repeat expansion in patients with hereditary spinocerebellar ataxia from Chinese kindreds. Arch Neurol,2000, 57(4):540.
[3]Okamoto T, Taniwaki M, et al.CAG expansions in a novel gene for Machado-Joseph disease at chromosome 14q32.1.Nat Genet,1994,8(3):221-8.
[4]Evidente VG, Gwinn-Hardy KA, Caviness JN, et al.Hereditary ataxias. Mayo Clin Proc. Mayo Clinic,2000,75(5):475-90.
[5]Zhou YX, Wang GX, Tang BS,et al.Spinocerebellar ataxia type 2 in China: molecular analysis and genotype-phenotype correlation in nine families. Neurology,1998,51(2):595-8.
[6]Orr HT, Zoghbi HY. Trinucleotide repeat disorders.Annu Rev Neurosci,2007, 30:575-621.
[7]Lin X, Cummings CJ, Zoghbi HY. Expanding our understanding of polyglutamine diseases through mouse models.Neuron,1999,24(3):499-502.
[8]Zoghbi HY, Orr HT. Polyglutamine diseases:protein cleavage and aggregation. Curr Opin Neurobiol,1999,9(5):566-70.
[9]Williams A, Jahreiss L, Sarkar S,et al.Aggregate-prone proteins are cleared from the cytosol by autophagy:therapeutic implications.Curr Top Dev Biol, 2006,76:89-101.
[10]Steffan JS,Thompson LM.Targeting aggregation in the development of therapeutics for the treatment of Huntington's disease and other polyglutamine repeat diseases.Expert Opin Ther Targets,2003,7(2):201-13.
[11]Li Y, Yokota T, Matsumura R, et al.Sequence-dependent and independent inhibition specific for mutant ataxin-3 by small interfering RNA. Ann Neurol, 2004,56(1):124-9.
[12]Xia J, Lee DH, Taylor J, et al. Huntingtin contains a highly conserved nuclear export signal.Hum Mol Genet,2003,12(12):1393-403.
[13]Schilling G, Savonenko AV, Klevytska A, et al.Nuclear-targeting of mutant huntingtin fragments produces Huntington's disease-like phenotypes in transgenic mice. Hum Mol Genet,2004,13(15):1599-610.
[14]Michalik A, Van Broeckhoven C.Pathogenesis of polyglutamine disorders: aggregation revisited. Hum Mol Genet,2003,12 Spec No 2:R173-86.
[15]Tarlac V, Storey E. Role of proteolysis in polyglutamine disorders. J Neurosci Res,2003,74(3):406-16.
[16]Takahashi T, Nozaki K, Tsuji S, et al. Polyglutamine represses cAMP-responsive-element-mediated transcription without aggregate formation. Neuroreport,2005,16(3):295-9.
[17]Arrasate M, Mitra S, Schweitzer ES,et al. Inclusion body formation reduces levels of mutant huntingtin and the risk of neuronal death. Nature,2004, 431(7010):805-10.
[18]Li LB,Yu Z, Teng X, et al. RNA toxicity is a component of ataxin-3 degeneration in Drosophila. Nature,2008,453(7198):1107-11.
[19]U M, Miyashita T, Ohtsuka Y, et al. Extended polyglutamine selectively interacts with caspase-8 and-10 in nuclear aggregates. Cell Death Differ,2001, 8(4):377-86.
[20]Ikeda H, Yamaguchi M, Sugai S,et al.Expanded polyglutamine in the Machado-Joseph disease protein induces cell death in vitro and in vivo. Nat Genet,1996,13(2):196-202.
[21]Wellington CL, Ellerby LM, Hackam AS,et al.Caspase cleavage of gene products associated with triplet expansion disorders generates truncated fragments containing the polyglutamine tract. J Biol Chem,1998, 273(15):9158-67.
[22]Berke SJ, Schmied FA, Brunt ER, et al.Caspase-mediated proteolysis of the polyglutamine disease protein ataxin-3.J Neurochem,2004,89(4):908-18.
[23]Margolis RL. Dominant spinocerebellar ataxias:a molecular approach to classification, diagnosis, pathogenesis and the future. Expert Rev Mol Diagn, 2003,3(6):715-32.
[24]Ross CA, Poirier MA. Protein aggregation and neurodegenerative disease. Nat Med,2004,10 Suppl:S10-7.
[25]Palladino MJ, Hadley TJ, Ganetzky B.Temperature-sensitive paralytic mutants are enriched for those causing neurodegeneration in Drosophila. Genetics,2002, 161(3):1197-208.
[26]Van Raamsdonk JM, Warby SC, Hayden MR. Selective degeneration in YAC mouse models of Huntington disease. Brain Res Bull,2007,72(2-3):124-31.
[27]Hodgson JG, Agopyan N, Gutekunst CA, et al. A YAC mouse model for Huntington's disease with full-length mutant huntingtin, cytoplasmic toxicity, and selective striatal neurodegeneration. Neuron,1999,23(1):181-92.
[28]Klement IA, Skinner PJ, Kaytor MD, et al.Ataxin-1 nuclear localization and aggregation:role in polyglutamine-induced disease in SCA1 transgenic mice. Cell,1998,95(1):41-53.
[29]Saudou F, Finkbeiner S,Devys D, et al.Huntingtin acts in the nucleus to induce apoptosis but death does not correlate with the formation of intranuclear inclusions.Cell,1998,95(1):55-66.
[30]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(4):879-92.
[31]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):673-82.
[32]van Groen T, Liu L, Ikonen S,et al.Diffuse amyloid deposition, but not plaque number, is reduced in amyloid precursor protein/presenilin 1 double-transgenic mice by pathway lesions. Neuroscience,2003,119(4):1185-97.
[33]Permanne B, Adessi C, Saborio GP, et al.Reduction of amyloid load and cerebral damage in a transgenic mouse model of Alzheimer's disease by treatment with a beta-sheet breaker peptide. FASEB J,2002,16(8):860-2.
[34]Chai Y, Koppenhafer SL, Bonini NM, et al.Analysis of the role of heat shock protein (Hsp) molecular chaperones in polyglutamine disease. J Neurosci,1999, 19(23):10338-47.
[35]Tajima H, Tsuchiya K, Yamada M, et al.Over-expression of GAPDH induces apoptosis in COS-7 cells transfected with cloned GAPDH cDNAs. Neuroreport, 1999,10(10):2029-33.
[36]Cooper AJ,Sheu KF, Burke JR, et al.Glyceraldehyde 3-phosphate dehydrogenase abnormality in metabolically stressed Huntington disease fibroblasts. Dev Neurosci,1998,20(4-5):462-8.
[37]Igarashi S,Koide R, Shimohata T, et al.Suppression of aggregate formation and apoptosis by transglutaminase inhibitors in cells expressing truncated DRPLA protein with an expanded polyglutamine stretch. Nat Genet,1998,18(2):111-7.
[38]Goldberg YP, Nicholson DW, Rasper DM, et al. Cleavage of huntingtin by apopain, a proapoptotic cysteine protease, is modulated by the polyglutamine tract. Nat Genet,1996,13(4):442-9.
[39]Sanchez I, Xu CJ, Juo P, et al. Caspase-8 is required for cell death induced by expanded polyglutamine repeats. Neuron,1999,22(3):623-33.
[40]Lonze BE, Ginty DD.Function and regulation of CREB family transcription factors in the nervous system. Neuron,2002,35(4):605-23.
[41]Mantamadiotis T, Lemberger T, Bleckmann SC, et al. Disruption of CREB function in brain leads to neurodegeneration. Nat Genet,2002,31(1):47-54.
[42]Collingwood TN, Urnov FD, Wolffe AP.Nuclear receptors:coactivators, corepressors and chromatin remodeling in the control of transcription. J Mol Endocrinol,1999,23(3):255-75.
[43]Shimohata T, Nakajima T, Yamada M, et al. Expanded polyglutamine stretches interact with TAFII130, interfering with CREB-dependent transcription. Nat Genet,2000,26(1):29-36.
[44]McCampbell A, Taylor JP, Taye AA, et al.CREB-binding protein sequestration by expanded polyglutamine. Hum Mol Genet,2000,9(14):2197-202.
[45]Li F, Macfarlan T, Pittman RN, et al.Ataxin-3 is a histone-binding protein with two independent transcriptional corepressor activities. J Biol Chem,2002, 277(47):45004-12.
[46]Steffan JS,Kazantsev A, Spasic-Boskovic O, et al.The Huntington's disease protein interacts with p53 and CREB-binding protein and represses transcription. Proc Natl Acad Sci,2000,97(12):6763-8.
[47]Evert BO, Araujo J, Vieira-Saecker AM, et al. Ataxin-3 represses transcription via chromatin binding, interaction with histone deacetylase 3,and histone deacetylation. J Neurosci,2006,26(44):11474-86.
[48]Yang XJ, Seto E. Collaborative spirit of histone deacetylases in regulating chromatin structure and gene expression. Curr Opin Genet Dev,2003, 13(2):143-53.
[49]Saha RN, Pahan K. HATs and HDACs in neurodegeneration:a tale of disconcerted acetylation homeostasis.Cell Death Differ,2006,13(4):539-50.
[50]Steffan JS,Bodai L, Pallos J, et al.Histone deacetylase inhibitors arrest polyglutamine-dependent neurodegeneration in Drosophila. Nature,2001, 413(6857):739-43.
[51]Bates EA, Victor M, Jones AK, et al. Differential contributions of Caenorhabditis elegans histone deacetylases to huntingtin polyglutamine toxicity. J Neurosci,2006,26(10):2830-8.
[52]Hockly E, Richon VM, Woodman B,et al. Suberoylanilide hydroxamic acid, a histone deacetylase inhibitor, ameliorates motor deficits in a mouse model of Huntington's disease. Proc Natl Acad Sci,2003,100(4):2041-6.
[53]Oliveira JM, Chen S,Almeida S,et al.Mitochondrial-dependent Ca2+ handling in Huntington's disease striatal cells:effect of histone deacetylase inhibitors. J Neurosci,2006,26(43):11174-86.
[54]Minamiyama M, Katsuno M, Adachi H, et al. Sodium butyrate ameliorates phenotypic expression in a transgenic mouse model of spinal and bulbar muscular atrophy. Hum Mol Genet,2004,13(11):1183-92.
[55]Katsuno M, Adachi H, Waza M, et al.Pathogenesis, animal models and therapeutics in spinal and bulbar muscular atrophy (SBMA). Exp Neurol,2006, 200(1):8-18.
[56]Ying M, Xu R, Wu X, et al. Sodium butyrate ameliorates histone hypoacetylation and neurodegenerative phenotypes in a mouse model for DRPLA.J Biol Chem,2006,281(18):12580-6.
[57]Kariya S, Hirano M, Uesato S,et al.Cytoprotective effect of novel histone deacetylase inhibitors against polyglutamine toxicity. Neurosci Lett,2006, 392(3):213-5.
[58]Johannessen CU. Mechanisms of action of valproate:a commentatory. Neurochem Int,2000,37(2-3):103-10.
[59]Lindhout D, Omtzigt JG. Pregnancy and the risk of teratogenicity. Epilepsia, 1992,33 Suppl 4:S41-8.
[60]Hsp22对SCA3/MJD转基因果蝇的神经保护作用研究。生物化学与生物物理进展,2008,35(12)：1430-1436。
[61]Butler R, Bates GP.Histone deacetylase inhibitors as therapeutics for polyglutamine disorders. Nat Rev Neurosci,2006,7(10):784-96.
[62]Ferrante RJ, Kubilus JK, Lee J, et al.Histone deacetylase inhibition by sodium butyrate chemotherapy ameliorates the neurodegenerative phenotype in Huntington's disease mice. J Neurosci,2003,23(28):9418-27.
[63]Chen PS, Peng GS, Li G, et al. Valproate protects dopaminergic neurons in midbrain neuron/glia cultures by stimulating the release of neurotrophic factors from astrocytes. Mol Psychiatry,2006,11(12):1116-25.
[64]Gottlicher M, Minucci S,Zhu P, et al. Valproic acid defines a novel class of HDAC inhibitors inducing differentiation of transformed cells. EMBO,2001, 20(24):6969-78.
[65]Kanai H, Sawa A, Chen RW, et al.Valproic acid inhibits histone deacetylase activity and suppresses excitotoxicity-induced GAPDH nuclear accumulation and apoptotic death in neurons. Pharmacogenomics,2004,4(5):336-44.
[66]Han R, Gao B,Sheng R, et al. Synergistic effects of prostaglandin E1 and lithium in a rat model of cerebral ischemia. Acta Pharmacol Sin,2008, 29(10):1141-9.
[67]Brichta L, Hofmann Y, Hahnen E, et al. Valproic acid increases the SMN2 protein level:a well-known drug as a potential therapy for spinal muscular atrophy. Hum Mol Genet,2003,12(19):2481-9.
[68]Kroetz MB, Su D, Hochstrasser M. Essential role of nuclear localization for yeast Ulp2 SUMO protease function. Mol Biol Cell,2009,20(8):2196-206.
[69]Kahyo T, Nishida T, Yasuda H. Involvement of PIAS1 in the sumoylation of tumor suppressor p53.Mol Cell,2001,8(3):713-8.
[70]Kerr JF, Wyllie AH, Currie AR. Apoptosis:a basic biological phenomenon with wide-ranging implications in tissue kinetics. Br J Cancer,1972,26(4):239-57.
[71]Zhong X, Pittman RN.Ataxin-3 binds VCP/p97 and regulates retrotranslocation of ERAD substrates.Hum Mol Genet,2006,15(16):2409-20.
[72]Dokucu ME, Yu L, Taghert PH.Lithium-and valproate-induced alterations in circadian locomotor behavior in Drosophila. Neuropsychopharmacology,2005, 30(12):2216-24.
[73]Carmichael J, Sugars KL, Bao YP,et al.Glycogen synthase kinase-3beta inhibitors prevent cellular polyglutamine toxicity caused by the Huntington's disease mutation. J Biol Chem,2002,277(37):33791-8.
[74]Wood NI, Morton AJ. Chronic lithium chloride treatment has variable effects on motor behaviour and survival of mice transgenic for the Huntington's disease mutation. Brain Res Bull,2003,61(4):375-83.
[75]Berger Z, Ttofi EK, Michel CH,et al.Lithium rescues toxicity of aggregate-prone proteins in Drosophila by perturbing Wnt pathway. Hum Mol Genet,2005,14(20):3003-11.
[76]Paulson HL, Bonini NM, Roth KA. Polyglutamine disease and neuronal cell death. Proc Natl Acad Sci,2000,97(24):12957-8.
[77]Bailey CD, Johnson GV. Tissue transglutaminase contributes to disease progression in the R6/2 Huntington's disease mouse model via aggregate-independent mechanisms. J Neurochem,2005,92(1):83-92.
[78]Karpuj MV, Becher MW, Springer JE, et al.Prolonged survival and decreased abnormal movements in transgenic model of Huntington disease, with administration of the transglutaminase inhibitor cystamine. Nat Med,2002, 8(2):143-9.
[79]Lesort M, Lee M, Tucholski J, et al.Cystamine inhibits caspase activity. Implications for the treatment of polyglutamine disorders.J Biol Chem,2003, 278(6):3825-30.
[80]Chuang DM. Neuroprotective and neurotrophic actions of the mood stabilizer lithium:can it be used to treat neurodegenerative diseases? Crit Rev Neurobiol, 2004,16(1-2):83-90.
[81]Nonaka S, Chuang DM.Neuroprotective effects of chronic lithium on focal cerebral ischemia in rats. Neuroreport,1998,9(9):2081-4.
[82]Hashimoto R, Hough C, Nakazawa T, et al.Lithium protection against glutamate excitotoxicity in rat cerebral cortical neurons:involvement of NMDA receptor inhibition possibly by decreasing NR2B tyrosine phosphorylation. J Neurochem, 2002,80(4):589-97.
[83]Leng Y, Chuang DM. Endogenous alpha-synuclein is induced by valproic acid through histone deacetylase inhibition and participates in neuroprotection against glutamate-induced excitotoxicity. J Neurosci,2006,26(28):7502-12.
[84]Nightingale KP, Wellinger RE, Sogo JM, et al.Histone acetylation facilitates RNA polymerase Ⅱ transcription of the Drosophila hsp26 gene in chromatin. EMBO J,1998,17(10):2865-76.
[85]Reid JL, lyer VR, Brown PO, et al.Coordinate regulation of yeast ribosomal protein genes is associated with targeted recruitment of Esal histone acetylase. Mol Cell,2000,6(6):1297-307.
[86]Bijur GN, Jope RS.Opposing actions of phosphatidylinositol 3-kinase and glycogen synthase kinase-3beta in the regulation of HSF-1 activity. J Neurochem,2000,75(6):2401-8.
[87]De Sarno P, Li X, Jope RS.Regulation of Akt and glycogen synthase kinase-3 beta phosphorylation by sodium valproate and lithium. Neuropharmacology, 2002,43(7):1158-64.
[88]Ren M, Leng Y, Jeong M, et al. Valproic acid reduces brain damage induced by transient focal cerebral ischemia in rats:potential roles of histone deacetylase inhibition and heat shock protein induction. J Neurochem,2004,89(6):1358-67.
[89]Chen T, Sun H, Lu J, et al. Histone acetylation is involved in hsp70 gene transcription regulation in Drosophila melanogaster. Arch Biochem Biophys, 2002,408(2):171-6.
[90]Tatar M, Khazaeli AA, Curtsinger JW. Chaperoning extended life. Nature,1997, 390(6655):30.
[91]Kurapati R, Passananti HB, Rose MR, et al. Increased hsp22 RNA levels in Drosophila lines genetically selected for increased longevity. J Gerontol A Biol Sci Med Sci,2000,55(11):B552-9.
[92]King V, Tower J.Aging-specific expression of Drosophila hsp22.Dev Biol, 1999,207(1):107-18.
[93]Wheeler JC, Bieschke ET, Tower J.Muscle-specific expression of Drosophila hsp70 in response to aging and oxidative stress. Proc Natl Acad Sci,1995, 92(22):10408-12.
[94]Hartl FU.Molecular chaperones in cellular protein folding. Nature,1996, 381(6583):571-9.
[95]Marin R, Valet JP, Tanguay RM. hsp23 and hsp26 exhibit distinct spatial and temporal patterns of constitutive expression in Drosophila adults. Dev Genet, 1993,14(1):69-77.
[96]Burnett BG, Pittman RN.The polyglutamine neurodegenerative protein ataxin 3 regulates aggresome formation. Proc Natl Acad Sci,2005,102(12):4330-5.
[97]Lengyel JA, Iwaki DD. It takes guts:the Drosophila hindgut as a model system for organogenesis. Dev Biol,2002,243(1):1-19.
[98]St Johnston D. The art and design of genetic screens:Drosophila melanogaster. Nat Rev Genet. Genetics,2002,3(3):176-88.
[99]Rubin GM, Lewis EB.A brief history of Drosophila's contributions to genome research. Science,2000,287(5461):2216-8.
[100]Reiter LT, Potocki L, Chien S,et al.A systematic analysis of human disease-associated gene sequences in Drosophila melanogaster. Genome Res,
2001,11(6):1114-25.
[101]O'Kane CJ. Modelling human diseases in Drosophila and Caenorhabditis. Semin Cell Dev Biol,2003,14(1):3-10.
[102]Muller A, MacCallum RM, Sternberg MJ. Structural characterization of the human proteome. Genome Res,2002,12(11):1625-41.
[103]Phelps CB, Brand AH.Ectopic gene expression in Drosophila using GAL4 system.Methods,1998,14(4):367-79.
[104]Spradling AC, Rubin GM. Transposition of cloned P elements into Drosophila germ line chromosomes.Science.1982,218(4570):341-7.
[105]Searles LL, Greenleaf AL, Kemp WE, et al.Sites of P element insertion and structures of P element deletions in the 5' region of Drosophila melanogaster RpII215.Mol Cell Bio,1986,6(10):3312-9.
[106]O'Hare K, Rubin GM. Structures of P transposable elements and their sites of insertion and excision in the Drosophila melanogaster genome. Cell,1983, 34(1):25-35.
[107]Warrick JM, Paulson HL, Gray-Board GL, et al. Expanded polyglutamine protein forms nuclear inclusions and causes neural degeneration in Drosophila. Cell,1998,93(6):939-49.
[108]Ellis MC, O'Neill EM, Rubin GM. Expression of Drosophila glass protein and evidence for negative regulation of its activity in non-neuronal cells by another DNA-binding protein; Expression of Drosophila glass protein and evidence for negative regulation of its activity in non-neuronal cells by another DNA-binding protein. Development,1993,119;119(3;3):855-65;855-65.
[109]Robinow S, White K. The locus elav of Drosophila melanogaster is expressed in neurons at all developmental stages.Dev Biol,1988,126(2):294-303.
[110]Kim YT, Shin SM, Lee WY, et al. Expression of expanded polyglutamine protein induces behavioral changes in Drosophila (polyglutamine-induced changes in Drosophila).Cell Mol Neurobiol,2004,24(1):109-22.
[111]Ghosh S,Feany MB.Comparison of pathways controlling toxicity in the eye and brain in Drosophila models of human neurodegenerative diseases. Hum Mol Genet,2004,13(18):2011-8.
[112]Warrick JM, Chan HY, Gray-Board GL, et al. Suppression of polyglutamine-mediated neurodegeneration in Drosophila by the molecular chaperone HSP70. Nat Genet,1999,23(4):425-8.
[113]Yoshizawa T, Yamagishi Y, Koseki N, et al. Cell cycle arrest enhances the in vitro cellular toxicity of the truncated Machado-Joseph disease gene product with an expanded polyglutamine stretch. Hum Mol Genet,2000,9(1):69-78.
[114]Yoshizawa T, Yoshida H, Shoji S.Differential susceptibility of cultured cell lines to aggregate formation and cell death produced by the truncated Machado-Joseph disease gene product with an expanded polyglutamine stretch. Brain Res Bull,2001,56(3-4):349-52.
[115]Jackson GR, Salecker I, Dong X, et al. Polyglutamine-expanded human huntingtin transgenes induce degeneration of Drosophila photoreceptor neurons. Neuron,1998,21(3):633-42.
[116]Moulder KL, Onodera O, Burke JR, et al.Generation of neuronal intranuclear inclusions by polyglutamine-GFP:analysis of inclusion clearance and toxicity as a function of polyglutamine length. J Neurosc,1999,19(2):705-15.
[117]Turmaine M, Raza A, Mahal A, et al.Nonapoptotic neurodegeneration in a transgenic mouse model of Huntington's disease. Proc Natl Acad Sci,2000, 97(14):8093-7.
[118]Gershon H, Gershon D.Detection of inactive enzyme molecules in ageing organisms.Nature,1970,227(5264):1214-7.
[119]Stadtman ER. Protein oxidation and aging. Science,1992,257(5074):1220-4.
[120]Paulson HL. Protein fate in neurodegenerative proteinopathies:polyglutamine diseases join the (mis)fold. Am J Hum Genet,1999,64(2):339-45.
[121]Koshy BT, Zoghbi HY. The CAG/polyglutamine tract diseases:gene products and molecular pathogenesis.Brain Pathol,1997,7(3):927-42.
[122]Durr A, Stevanin G, Cancel G, et al.Spinocerebellar ataxia 3 and Machado-Joseph disease:clinical, molecular, and neuropathological features. Ann Neural,1996,39(4):490-9.
[123]Zhao Y, Sun H, Lu J, et al.Lifespan extension and elevated hsp gene expression in Drosophila caused by histone deacetylase inhibitors.J Exp Biol,2005,208(Pt 4):697-705.
[1]Bates G. Huntingtin aggregation and toxicity in Huntington's disease. Lancet, 2003,361(9369):1642-4.
[2]Koide R, Ikeuchi T, Onodera O, et al. Unstable expansion of CAG repeat in hereditary dentatorubral-pallidoluysian atrophy (DRPLA).Nat Genet, 1994,6(1):9-13.
[3]Nagafuchi S,Yanagisawa H, Sato K, et al.Dentatorubral and pallidoluysian atrophy expansion of an unstable CAG trinucleotide on chromosome 12p. Nat Genet,1994,6(1):14-8.
[4]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(6):971-83.
[5]La Spada AR, Wilson EM, Lubahn DB, et al.Androgen receptor gene mutations in X-linked spinal and bulbar muscular atrophy. Naturee,1991,352(6330):77-9.
[6]Orr HT, Chung MY, Banfi S,et al.Expansion of an unstable trinucleotide CAG repeat in spinocerebellar ataxia type 1.Nat Genet,1993,4(3):221-6.
[7]Imbert G, Saudou F, Yvert G, et al. Cloning of the gene for spinocerebellar ataxia 2 reveals a locus with high sensitivity to expanded CAG/glutamine repeats. Nat Genet,1996,14(3):285-91.
[8]Pulst SM, Nechiporuk A, Nechiporuk T, et al.Moderate expansion of a normally biallelic trinucleotide repeat in spinocerebellar ataxia type 2.Nat Genet,1996, 14(3):269-76.
[9]Sanpei K, Takano H, Igarashi S,et al.Identification of the spinocerebellar ataxia type 2 gene using a direct identification of repeat expansion and cloning technique, DIRECT. Nat Genet,1996,14(3):277-84.
[10]Matilla T, McCall A, Subramony SH, et al.Molecular and clinical correlations in spinocerebellar ataxia type 3 and Machado-Joseph disease. Ann Neurol,1995, 38(1):68-72.
[11]Kawaguchi Y, Okamoto T, Taniwaki M, et al.CAG expansions in a novel gene for Machado-Joseph disease at chromosome 14q32.1.Nat Genet,1994, 8(3):221-8.
[12]Zhuchenko O, Bailey J, Bonnen P, et al. Autosomal dominant cerebellar ataxia (SCA6) associated with small polyglutamine expansions in the alpha 1A-voltage-dependent calcium channel.Nat Genet,1997,15(1):62-9.
[13]Chung MY, Lu YC, Cheng NC, et al. A novel autosomal dominant spinocerebellar ataxia (SCA22) linked to chromosome 1p21-q23.Brain,2003, 126(Pt 6):1293-9.
[14]Nakamura K, Jeong SY, Uchihara T, et al.SCA17, a novel autosomal dominant cerebellar ataxia caused by an expanded polyglutamine in TATA-binding protein. Hum Mol Genet,2001,10(14):1441-8.
[15]David G, Abbas N, Stevanin G, et al.Cloning of the SCA7 gene reveals a highly unstable CAG repeat expansion. Nat Genet,1997,17(1):65-70.
[16]Williams A, Jahreiss L, Sarkar S, et al. Aggregate-prone proteins are cleared from the cytosol by autophagy:therapeutic implications. Curr Top Dev Biol, 2006,76:89-101.
[17]Steffan JS, Thompson LM. Targeting aggregation in the development of therapeutics for the treatment of Huntington's disease and other polyglutamine repeat diseases. Expert Opin Ther Targets,2003,7(2):201-13.
[18]Li Y, Yokota T, Matsumura R, et al. Sequence-dependent and independent inhibition specific for mutant ataxin-3 by small interfering RNA. Ann Neurol, 2004,56(1):124-9.
[19]Xia J, Lee DH, Taylor J, et al.Huntingtin contains a highly conserved nuclear export signal.Hum Mol Genet,2003,12(12):1393-403.
[20]Schilling G, Savonenko AV, Klevytska A, et al.Nuclear-targeting of mutant huntingtin fragments produces Huntington's disease-like phenotypes in transgenic mice. Hum Mol Genet,2004,13(15):1599-610.
[21]Michalik A, Van Broeckhoven C. Pathogenesis of polyglutamine disorders: aggregation revisited. Hum Mol Genet,2003,12 Spec No 2:R173-86.
[22]Tarlac V, Storey E.Role of proteolysis in polyglutamine disorders. J Neurosci Res,2003,74(3):406-16.
[23]Takahashi T, Nozaki K, Tsuji S,et al.Polyglutamine represses cAMP-responsive-element-mediated transcription without aggregate formation. Neuroreport,2005,16(3):295-9.
[24]Arrasate M, Mitra S, Schweitzer ES,et al.Inclusion body formation reduces levels of mutant huntingtin and the risk of neuronal death. Nature,2004, 431(7010):805-10.
[25]Li LB, Yu Z, Teng X, et al. RNA toxicity is a component of ataxin-3 degeneration in Drosophila. Nature,2008,453(7198):1107-11.
[26]U M, Miyashita T, Ohtsuka Y, et al. Extended polyglutamine selectively interacts with caspase-8 and-10 in nuclear aggregates. Cell Death Differ,2001, 8(4):377-86.
[27]Ikeda H, Yamaguchi M, Sugai S, et al.Expanded polyglutamine in the Machado-Joseph disease protein induces cell death in vitro and in vivo. Nat Genet,1996,13(2):196-202.
[28]Wellington CL, Ellerby LM, Hackam AS, et al.Caspase cleavage of gene products associated with triplet expansion disorders generates truncated fragments containing the polyglutamine tract. J Biol Chem,1998, 273(15):9158-67.
[29]Berke SJ, Schmied FA, Brunt ER, et al.Caspase-mediated proteolysis of the polyglutamine disease protein ataxin-3.J Neurochem,2004,89(4):908-18.
[30]Margolis RL. Dominant spinocerebellar ataxias:a molecular approach to classification, diagnosis, pathogenesis and the future. Expert Rev Mol Diagn, 2003,3(6):715-32.
[31]Ross CA, Poirier MA. Protein aggregation and neurodegenerative disease. Nat Med,2004,10 Suppl:S10-7.
[32]Duenas AM, Goold R, Giunti P.Molecular pathogenesis of spinocerebellar ataxias. Brain,2006,129(Pt 6):1357-70.
[33]Van Raamsdonk JM, Warby SC, Hayden MR. Selective degeneration in YAC mouse models of Huntington disease. Brain Res Bull,2007,72(2-3):124-31.
[34]Hodgson JG, Agopyan N, Gutekunst CA, et al.A YAC mouse model for Huntington's disease with full-length mutant huntingtin, cytoplasmic toxicity, and selective striatal neurodegeneration. Neuron,1999,23(1):181-92.
[35]Klement IA, Skinner PJ, Kaytor MD, et al.Ataxin-1 nuclear localization and aggregation:role in polyglutamine-induced disease in SCA1 transgenic mice. Cell,1998,95(1):41-53.
[36]Saudou F, Finkbeiner S,Devys D, et al. Huntingtin acts in the nucleus to induce apoptosis but death does not correlate with the formation of intranuclear inclusions. Cell,1998,95(1):55-66.
[37]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(4):879-92.
[38]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):673-82.
[39]van Groen T, Liu L, lkonen S,et al.Diffuse amyloid deposition, but not plaque number, is reduced in amyloid precursor protein/presenilin 1 double-transgenic mice by pathway lesions. Neuroscience,2003,119(4):1185-97.
[40]Permanne B, Adessi C, Saborio GP, et al. Reduction of amyloid load and cerebral damage in a transgenic mouse model of Alzheimer's disease by treatment with a beta-sheet breaker peptide. FASEB J,2002,16(8):860-2.
[41]Chai Y, Koppenhafer SL, Bonini NM, et al.Analysis of the role of heat shock protein (Hsp) molecular chaperones in polyglutamine disease. J Neurosci,1999, 19(23):10338-47.
[42]Tajima H, Tsuchiya K, Yamada M, et al. Over-expression of GAPDH induces apoptosis in COS-7 cells transfected with cloned GAPDH cDNAs. Neuroreport, 1999,10(10):2029-33.
[43]Cooper AJ, Sheu KF, Burke JR, et al.Glyceraldehyde 3-phosphate dehydrogenase abnormality in metabolically stressed Huntington disease fibroblasts.Dev Neurosci,1998,20(4-5):462-8.
[44]Igarashi S,Koide R, Shimohata T, et al. Suppression of aggregate formation and apoptosis by transglutaminase inhibitors in cells expressing truncated DRPLA protein with an expanded polyglutamine stretch. Nat Genet,1998,18(2):111-7.
[45]Goldberg YP,Nicholson DW, Rasper DM, et al.Cleavage of huntingtin by apopain, a proapoptotic cysteine protease, is modulated by the polyglutamine tract. Nat Genet,1996,13(4):442-9.
[46]Sanchez I, Xu CJ, Juo P, et al.Caspase-8 is required for cell death induced by expanded polyglutamine repeats. Neuron,1999,22(3):623-33.
[47]Turner BM. Histone acetylation and an epigenetic code. Bioessays, 2000,22(9):836-45.
[48]Taddei A, Roche D, Sibarita JB, et al.Duplication and maintenance of heterochromatin domains. J Cell Biol,1999,47(6):1153-66.
[49]Taylor JP, Fischbeck KH. Altered acetylation in polyglutamine disease:an opportunity for therapeutic intervention? Trends Mol Med,2002,8(5):195-7.
[50]Kouzarides T. Histone acetylases and deacetylases in cell proliferation. Curr Opin Genet Dev,1999,9(1):40-8.
[51]Yang XJ, Seto E. Collaborative spirit of histone deacetylases in regulating chromatin structure and gene expression. Curr Opin Genet Dev,2003, 13(2):143-53.
[52]Saha RN, Pahan K. HATs and HDACs in neurodegeneration:a tale of disconcerted acetylation homeostasis. Cell Death Differ,2006,13(4):539-50.
[53]Chang KT,Min KT. Regulation of lifespan by histone deacetylase. Ageing Res Rev,2002,1(3):313-26.
[54]Lin T, Chen H, Koustova E, et al.Histone deacetylase as therapeutic target in a rodent model of hemorrhagic shock:effect of different resuscitation strategies on lung and liver. Surgery,2007,141(6):784-94.
[55]Antoniu SA. Histone deacetylase pathway:an evolving therapeutic target in chronic obstructive pulmonary disease. Expert Opin Ther Targets,2006, 10(2):329-32.
[56]Kramer OH, Gottlicher M, Heinzel T. Histone deacetylase as a therapeutic target. Trends Endocrinol Metab,2001,12(7):294-300.
[57]Marks PA, Richon VM, Breslow R, et al.Histone deacetylase inhibitors as new cancer drugs.Curr Opin Oncol,2001,13(6):477-83.
[58]Brusilow SW, Danney M, Waber LJ, et al.Treatment of episodic hyperammonemia in children with inborn errors of urea synthesis.N Engl J Med, 1984,310(25):1630-4.
[59]Melchior SW, Brown LG, Figg WD,et al.Effects of phenylbutyrate on proliferation and apoptosis in human prostate cancer cells in vitro and in vivo. Int J Oncol,1999,14(3):501-8.
[60]Perrine SP,Ginder GD,Faller DV,et al.A short-term trial of butyrate to stimulate fetal-globin-gene expression in the beta-globin disorders. N Engl J Med,1993,328(2):81-6.
[61]Kemp S,Wei HM, Lu JF, et al.Gene redundancy and pharmacological gene therapy:implications for X-linked adrenoleukodystrophy. Nat Med,1998, 4(11):1261-8.
[62]Rubenstein RC, Zeitlin PL. A pilot clinical trial of oral sodium 4-phenylbutyrate (Buphenyl) in deltaF508-homozygous cystic fibrosis patients:partial restoration of nasal epithelial CFTR function. Am J Respir Crit Care Med,1998, 157(2):484-90.
[63]Chiurazzi P, Pomponi MG, Pietrobono R, et al.Synergistic effect of histone hyperacetylation and DNA demethylation in the reactivation of the FMR1 gene. Hum Mol Genet,1999,8(12):2317-23.
[64]Lonze BE, Ginty DD. Function and regulation of CREB family transcription factors in the nervous system. Neuron,2002,35(4):605-23.
[65]Mantamadiotis T, Lemberger T, Bleckmann SC, et al.Disruption of CREB function in brain leads to neurodegeneration. Nat Genet,2002,31(1):47-54.
[66]Shimohata T, Nakajima T, Yamada M, et al. Expanded polyglutamine stretches interact with TAFII130, interfering with CREB-dependent transcription. Nat Genet,2000,26(1):29-36.
[67]Sapp E, Ge P, Aizawa H, et al.Evidence for a preferential loss of enkephalin immunoreactivity in the external globus pallidus in low grade Huntington's disease using high resolution image analysis. Neuroscience,1995, 64(2):397-404.
[68]De Souza EB,Whitehouse PJ, Folstein SE, et al.Corticotropin-releasing hormone (CRH) is decreased in the basal ganglia in Huntington's disease. Brain Res,1987,437(2):355-9.
[69]Luthi-Carter R, Strand A, Peters NL, et al.Decreased expression of striatal signaling genes in a mouse model of Huntington's disease. Hum Mol Genet, 2000,9(9):1259-71.
[70]Cha JH, Frey AS,Alsdorf SA, et al.Altered neurotransmitter receptor expression in transgenic mouse models of Huntington's disease. Philos Trans R Soc Lond B Biol Sci.Series B,Biological sciences,1999,354(1386):981-9.
[71]Walton MR, Dragunow I.Is CREB a key to neuronal survival? Trends Neurosci, 2000,23(2):48-53.
[72]Li SH, Cheng AL, Li H, et al.Cellular defects and altered gene expression in PC 12 cells stably expressing mutant huntingtin. J Neurosci,1999, 19(13):5159-72.
[73]Wyttenbach A, Swartz J, Kita H,et al.Polyglutamine expansions cause decreased CRE-mediated transcription and early gene expression changes prior to cell death in an inducible cell model of Huntington's disease. Hum Mol Genet,
2001,10(17):1829-45.
[74]Riccio A, Ahn S, Davenport CM, et al. Mediation by a CREB family transcription factor of NGF-dependent survival of sympathetic neurons. Science, 1999,286(5448):2358-61.
[75]McCampbell A, Taylor JP, Taye AA, et al. CREB-binding protein sequestration by expanded polyglutamine. Hum Mol Genet,2000,9(14):2197-202.
[76]Dunah AW, Jeong H, Griffin A, et al.Spl and TAFII130 transcriptional activity disrupted in early Huntington's disease. Science,2002,296(5576):2238-43.
[77]Taylor JP, Taye AA, Campbell C, et al.Aberrant histone acetylation, altered transcription, and retinal degeneration in a Drosophila model of polyglutamine disease are rescued by CREB-binding protein. Genes Dev,2003,17(12):1463-8.
[78]Li F, Macfarlan T, Pittman RN, et al. Ataxin-3 is a histone-binding protein with two independent transcriptional corepressor activities. J Biol Chem,2002, 277(47):45004-12.
[79]Steffan JS,Kazantsev A, Spasic-Boskovic O, et al.The Huntington's disease protein interacts with p53 and CREB-binding protein and represses transcription. Proc Natl Acad Sci,2000,97(12):6763-8.
[80]Evert BO, Araujo J, Vieira-Saecker AM, et al. Ataxin-3 represses transcription via chromatin binding, interaction with histone deacetylase 3,and histone deacetylation. J Neurosci,2006,26(44):11474-86.
[81]Rouaux C, Jokic N, Mbebi C, et al.Critical loss of CBP/p300 histone acetylase activity by caspase-6 during neurodegeneration. EMBO J,2003, 22(24):6537-49.
[82]Jiang H, Nucifora FC Jr, Ross CA, et al.Cell death triggered by polyglutamine-expanded huntingtin in a neuronal cell line is associated with degradation of CREB-binding protein. Hum Mol Genet,2003,12(1):1-12.
[83]Oliveira JM, Chen S, Almeida S,et al.Mitochondrial-dependent Ca2+handling in Huntington's disease striatal cells:effect of histone deacetylase inhibitors. J Neurosci,2006,26(43):11174-86.
[84]Bates EA, Victor M, Jones AK, et al.Differential contributions of Caenorhabditis elegans histone deacetylases to huntingtin polyglutamine toxicity. J Neurosci,2006,26(10):2830-8.
[85]Steffan JS,Bodai L, Pallos J, et al.Histone deacetylase inhibitors arrest polyglutamine-dependent neurodegeneration in Drosophila. Nature,2001, 413(6857):739-43.
[86]Ferrante RJ, Kubilus JK, Lee J, et al.Histone deacetylase inhibition by sodium butyrate chemotherapy ameliorates the neurodegenerative phenotype in Huntington's disease mice. J Neurosci,2003,23(28):9418-27.
[87]Hockly E, Richon VM, Woodman B,et al. Suberoylanilide hydroxamic acid, a histone deacetylase inhibitor, ameliorates motor deficits in a mouse model of Huntington's disease. Proc Natl Acad Sci,2003,100(4):2041-6.
[88]McCampbell A, Taye AA, Whitty L, et al.Histone deacetylase inhibitors reduce polyglutamine toxicity. Proc Natl Acad Sci,2001,98(26):15179-84.
[89]Helmlinger D, Hardy S,Abou-Sleymane G, et al.Glutamine-expanded ataxin-7 alters TFTC/STAGA recruitment and chromatin structure leading to photoreceptor dysfunction. PLoS Biol,2006,4(3):e67.
[90]Palhan VB, Chen S, Peng GH, et al. Polyglutamine-expanded ataxin-7 inhibits STAGA histone acetyltransferase activity to produce retinal degeneration. Proc Natl Acad Sci,2005,102(24):8472-7.
[91]McMahon SJ, Pray-Grant MG, Schieltz D, et al. Polyglutamine-expanded spinocerebellar ataxia-7 protein disrupts normal SAGA and SLIK histone acetyltransferase activity. Proc Natl Acad Sci,2005,102(24):8478-82.
[92]Seo SB,McNamara P,Heo S,et al.Regulation of histone acetylation and transcription by INHAT, a human cellular complex containing the set oncoprotein. Cell,2001,104(1):119-30.
[93]Matilla A, Koshy BT, Cummings CJ, et al.The cerebellar leucine-rich acidic nuclear protein interacts with ataxin-1.Nature,1997,389(6654):974-8.
[94]Bolger TA, Zhao X, Cohen TJ, et al.The neurodegenerative disease protein ataxin-1 antagonizes the neuronal survival function of myocyte enhancer factor-2.J Biol Chem,2007,282(40):29186-92.
[95]Pray-Grant MG, Schieltz D, McMahon SJ,et al. The novel SLIK histone acetyltransferase complex functions in the yeast retrograde response pathway. Mol Cell Biol,2002,22(24):8774-86.
[96]Burnett BG, Pittman RN.The polyglutamine neurodegenerative protein ataxin 3 regulates aggresome formation. Proc Natl Acad Sci,2005,102(12):4330-5.
[97]Wood JD, Nucifora FC Jr, Duan K, et al.Atrophin-1, the dentato-rubral and pallido-luysian atrophy gene product, interacts with ETO/MTG8 in the nuclear matrix and represses transcription. J Cell Biol,2000,150(5):939-48.
[98]Kariya S,Hirano M, Uesato S, et al.Cytoprotective effect of novel histone deacetylase inhibitors against polyglutamine toxicity. Neurosci Lett,2006, 392(3):213-5.
[99]Ying M, Xu R, Wu X, et al. Sodium butyrate ameliorates histone hypoacetylation and neurodegenerative phenotypes in a mouse model for DRPLA. J Biol Chem,2006,281(18):12580-6.
[100]Minamiyama M, Katsuno M, Adachi H, et al.Sodium butyrate ameliorates phenotypic expression in a transgenic mouse model of spinal and bulbar muscular atrophy. Hum Mol Genet,2004,13(11):1183-92.
[101]Katsuno M, Adachi H, Waza M, et al.Pathogenesis, animal models and therapeutics in spinal and bulbar muscular atrophy (SBMA).Exp Neurol,2006, 200(1):8-18.