Cell-autonomous progeroid changes in conditional mouse models for repair endonuclease XPG deficiency.
Cell-autonomous progeroid changes in conditional mouse models for repair endonuclease XPG deficiency.
复制标题
DOI：
10.1371/journal.pgen.1004686
复制
发表时间：
2014-10
期刊：
影响因子：
4.5
通讯作者：
van der Pluijm I
中科院分区：
文献类型：
--
作者：
Barnhoorn S;Uittenboogaard LM;Jaarsma D;Vermeij WP;Tresini M;Weymaere M;Menoni H;Brandt RM;de Waard MC;Botter SM;Sarker AH;Jaspers NG;van der Horst GT;Cooper PK;Hoeijmakers JH;van der Pluijm I
作为核苷酸切除修复（NER）过程的一部分，内切酶XPG参与螺旋扭曲DNA损伤的修复，但该蛋白也涉及其他几种DNA修复系统，使XPG患者的基因型-表型关系复杂化。XPG缺陷可导致易发癌症的色素性干皮病（XP），或XP合并严重神经发育障碍科凯恩综合征（CS），或婴儿致死性脑-眼-面-骨骼（COFS）综合征，其特征是显著的生长衰竭，进行性神经发育异常和预期寿命大大缩短。在这里，我们提出了一种新的（条件）Xpg - / -小鼠模型，在C57BL6/FVB F1杂交遗传背景下，显示出许多类早衰特征，包括生长停止，皮下脂肪减少，后凸，骨质疏松，视网膜光受体丧失，肝脏老化，广泛的神经退行性变，以及4-5个月的短寿命。我们发现，肝脏中特异性的XPG缺失再现了肝脏中的类早衰特征，但消除了对生长或寿命的影响。此外，在前脑的神经元和胶质细胞中特异性的XPG缺失会产生进行性神经退行性表型，显示出人类XPG缺乏的许多特征。因此，我们的研究结果排除了肝脏和神经表型是其他细胞类型、器官或组织（例如血管异常）脱轨的次要后果，并支持由DNA修复缺陷本身引起的细胞自主起源。此外，它们还允许解剖组织和细胞类型特异性成分中复杂的衰老过程。此外，我们的数据强调了遗传背景在小鼠衰老研究中的重要性，建立了Xpg - / -小鼠作为人类严重Xpg患者和部分加速衰老的有效模型，并加强了DNA损伤与衰老之间的联系。DNA损伤的积累与衰老有关。许多早衰综合征是由于有缺陷的DNA修复系统。内切酶XPG参与螺旋扭曲DNA损伤的修复，而XPG缺陷可单独或合并严重的神经发育性早老性疾病科凯恩综合征（CS）导致易发癌症的色素干皮病（XP）。在这里，我们提出了一种新的（条件）Xpg - / -小鼠模型，在C57BL6/FVB F1杂交背景下，显示出许多进行性类早衰特征，包括早期停止生长，恶病质，后凸，骨质疏松，神经变性，肝脏老化，视网膜变性和寿命缩短。在具有复杂表型的组成型突变体中，很难分析原因和后果。因此，我们产生了肝脏和前脑特异性Xpg突变体，并证明它们分别表现出进行性异核病和神经变性，这表明神经元的细胞内在修复缺陷可以解释神经元变性。这些发现加强了DNA损伤和复杂的衰老过程之间的联系。
As part of the Nucleotide Excision Repair (NER) process, the endonuclease XPG is involved in repair of helix-distorting DNA lesions, but the protein has also been implicated in several other DNA repair systems, complicating genotype-phenotype relationship in XPG patients. Defects in XPG can cause either the cancer-prone condition xeroderma pigmentosum (XP) alone, or XP combined with the severe neurodevelopmental disorder Cockayne Syndrome (CS), or the infantile lethal cerebro-oculo-facio-skeletal (COFS) syndrome, characterized by dramatic growth failure, progressive neurodevelopmental abnormalities and greatly reduced life expectancy. Here, we present a novel (conditional) Xpg−/− mouse model which -in a C57BL6/FVB F1 hybrid genetic background- displays many progeroid features, including cessation of growth, loss of subcutaneous fat, kyphosis, osteoporosis, retinal photoreceptor loss, liver aging, extensive neurodegeneration, and a short lifespan of 4–5 months. We show that deletion of XPG specifically in the liver reproduces the progeroid features in the liver, yet abolishes the effect on growth or lifespan. In addition, specific XPG deletion in neurons and glia of the forebrain creates a progressive neurodegenerative phenotype that shows many characteristics of human XPG deficiency. Our findings therefore exclude that both the liver as well as the neurological phenotype are a secondary consequence of derailment in other cell types, organs or tissues (e.g. vascular abnormalities) and support a cell-autonomous origin caused by the DNA repair defect itself. In addition they allow the dissection of the complex aging process in tissue- and cell-type-specific components. Moreover, our data highlight the critical importance of genetic background in mouse aging studies, establish the Xpg−/− mouse as a valid model for the severe form of human XPG patients and segmental accelerated aging, and strengthen the link between DNA damage and aging. Accumulation of DNA damage has been implicated in aging. Many premature aging syndromes are due to defective DNA repair systems. The endonuclease XPG is involved in repair of helix-distorting DNA lesions, and XPG defects cause the cancer-prone condition xeroderma pigmentosum (XP) alone or combined with the severe neurodevelopmental progeroid disorder Cockayne syndrome (CS). Here, we present a novel (conditional) Xpg−/− mouse model which -in a C57BL6/FVB F1 hybrid background- displays many progressive progeroid features, including early cessation of growth, cachexia, kyphosis, osteoporosis, neurodegeneration, liver aging, retinal degeneration, and reduced lifespan. In a constitutive mutant with a complex phenotype it is difficult to dissect cause and consequence. We have therefore generated liver- and forebrain-specific Xpg mutants and demonstrate that they exhibit progressive anisokaryosis and neurodegeneration, respectively, indicating that a cell-intrinsic repair defect in neurons can account for neuronal degeneration. These findings strengthen the link between DNA damage and the complex process of aging.
登录
查看更多内容
影响因子：
14.5
作者：
El-Deiry, WS
通讯作者：
El-Deiry, WS
影响因子：
12.7
作者：
de Waard MC;van der Pluijm I;Zuiderveen Borgesius N;Comley LH;Haasdijk ED;Rijksen Y;Ridwan Y;Zondag G;Hoeijmakers JH;Elgersma Y;Gillingwater TH;Jaarsma D
通讯作者：
Jaarsma D
DOI：
10.1007/s11357-011-9291-8
发表时间：
2012-08
期刊：
Age (Dordrecht, Netherlands)
影响因子：
--
作者：
Diderich KE;Nicolaije C;Priemel M;Waarsing JH;Day JS;Brandt RM;Schilling AF;Botter SM;Weinans H;van der Horst GT;Hoeijmakers JH;van Leeuwen JP
通讯作者：
van Leeuwen JP
影响因子：
3.8
作者：
de Waard, H;de Wit, J;van der Horst, GTJ
通讯作者：
van der Horst, GTJ
影响因子：
8
作者：
D'Errico, M.;Parlanti, E.;Dogliotti, E.
通讯作者：
Dogliotti, E.