A Large Number of Protein Expression Changes Occur Early in Life and Precede Phenotype Onset in a Mouse Model for Huntington Disease*S
A Large Number of Protein Expression Changes Occur Early in Life and Precede Phenotype Onset in a Mouse Model for Huntington Disease*S
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在亨廷顿病小鼠模型中，大量蛋白质表达变化发生在生命早期并先于表型出现*S
DOI：
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发表时间：
2009
影响因子：
7
通讯作者：
G. Bates
中科院分区：
文献类型：
--
作者：
C. Zabel;L. Mao;B. Woodman;Michael Rohe;Maik A. Wacker;Y. Kläre;Andrea Koppelstätter;G. Nebrich;O. Klein;S. Grams;AndrewD . Strand;R. Luthi;D. Hartl;J. Klose;G. Bates
亨廷顿病(HD)在人类有症状的15-20年内是致命的。虽然晚期HD已经得到了广泛的研究，但在疾病早期和疾病进展过程中发生的蛋白质表达变化尚未见报道。在这项研究中，我们使用了一种基于二维凝胶/质谱学的大型蛋白质组学方法来研究HD诱导的蛋白质表达变化及其在疾病早期和病程中的动力学。分别在2、4、6、8和12周龄时研究小鼠HD模型R6/2，对应于无疾病和早、中、晚期HD。出乎意料的是，最具HD阶段特异性的蛋白质变化(71-100%)以及蛋白质表达的剧烈变化(几乎占蛋白质组的6%)早在2周龄就已经发生了。早期的变化主要包括糖酵解/糖异生相关蛋白的上调和肌动蛋白细胞骨架的下调。这表明在HD表型开始之前有一段高度可变的蛋白质表达时期。虽然糖酵解/糖异生相关的蛋白改变在HD进展中仍占主导地位，但在12周的晚期改变显示参与蛋白酶体功能的蛋白上调。HD的早期变化与2周龄小鼠正常发育过程中蛋白质变化的高峰相吻合，这可能是导致这些巨大变化的原因。蛋白质和信使核糖核酸的数据集显示，在受影响的通路水平上有很大的重叠，但不是单一的蛋白质/mRNAs。我们的观察表明，HD的特点是高度动态的疾病病理，而不是表现为病程中蛋白质浓度的线性变化。
Huntington disease (HD) is fatal in humans within 15–20 years of symptomatic disease. Although late stage HD has been studied extensively, protein expression changes that occur at the early stages of disease and during disease progression have not been reported. In this study, we used a large two-dimensional gel/mass spectrometry-based proteomics approach to investigate HD-induced protein expression alterations and their kinetics at very early stages and during the course of disease. The murine HD model R6/2 was investigated at 2, 4, 6, 8, and 12 weeks of age, corresponding to absence of disease and early, intermediate, and late stage HD. Unexpectedly the most HD stage-specific protein changes (71–100%) as well as a drastic alteration (almost 6% of the proteome) in protein expression occurred already as early as 2 weeks of age. Early changes included mainly the up-regulation of proteins involved in glycolysis/gluconeogenesis and the down-regulation of the actin cytoskeleton. This suggests a period of highly variable protein expression that precedes the onset of HD phenotypes. Although an up-regulation of glycolysis/gluconeogenesis-related protein alterations remained dominant during HD progression, late stage alterations at 12 weeks showed an up-regulation of proteins involved in proteasomal function. The early changes in HD coincide with a peak in protein alteration during normal mouse development at 2 weeks of age that may be responsible for these massive changes. Protein and mRNA data sets showed a large overlap on the level of affected pathways but not single proteins/mRNAs. Our observations suggest that HD is characterized by a highly dynamic disease pathology not represented by linear protein concentration alterations over the course of disease.
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影响因子：
--
作者：
C. Zabel;J. Klose
通讯作者：
C. Zabel;J. Klose
影响因子：
9.8
作者：
D. Rubinsztein;J. Leggo;Rhian;Coles;E. Almqvist;V. Biancalana;J. Cassiman;K. Chotai;Margaret;Connarty;D. Craufurd;A. Curtis;D. Curtis;M. Davidson;C. Dodé;A. Dodge;M. Frontali;N. Ranen;C. Stine;M. Sherr;M. Abbott;M. Franz;C. Graham;P. Harper;C. John;Hedreen;A. Jackson;M. Losekoot;J. MacMillan;P. Morrison;Y. Trottier;A. Novelletto;S. Simpson;'. J. Theilmann;L. Joanne;Whittaker;S. Folstein;C. Ross;M. Hayden
通讯作者：
D. Rubinsztein;J. Leggo;Rhian;Coles;E. Almqvist;V. Biancalana;J. Cassiman;K. Chotai;Margaret;Connarty;D. Craufurd;A. Curtis;D. Curtis;M. Davidson;C. Dodé;A. Dodge;M. Frontali;N. Ranen;C. Stine;M. Sherr;M. Abbott;M. Franz;C. Graham;P. Harper;C. John;Hedreen;A. Jackson;M. Losekoot;J. MacMillan;P. Morrison;Y. Trottier;A. Novelletto;S. Simpson;'. J. Theilmann;L. Joanne;Whittaker;S. Folstein;C. Ross;M. Hayden
神经系统遗传性疾病的分子治疗方法：以亨廷顿舞蹈病为范例。
影响因子：
13.9
作者：
Wexler,NS;Rose,EA;Housman,DE
通讯作者：
Housman,DE
影响因子：
3.5
作者：
Chan, EYW;Luthi-Carter, R;Olson, JM
通讯作者：
Olson, JM
影响因子：
3.5
作者：
Engelender, S;Sharp, AH;Ross, CA
通讯作者：
Ross, CA