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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Increased apoptosis, p53 up-regulation, and cerebellar neuronal degeneration in repair-deficient Cockayne syndrome mice
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Increased apoptosis, p53 up-regulation, and cerebellar neuronal degeneration in repair-deficient Cockayne syndrome mice

机译：修复缺陷型Cockayne综合征小鼠的凋亡增加，p53上调和小脑神经元变性

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摘要

Cockayne syndrome (CS) is a rare recessive childhood-onset neuroclegenerative disease, characterized by a deficiency in the DNA repair pathway of transcription-coupled nucleotide excision repair. Mice with a targeted deletion of the CSB gene (Csb(-/-)) exhibit a much milder ataxic phenotype than human patients. Csb(-/-) mice that are also deficient in global genomic repair [Csb(-/-)/xeroderma pigmentosum C(Xpc)(-/-)] are more profoundly affected, exhibiting whole-body wasting, ataxia, and neural loss by postnatal day 21. Cerebellar granule cells demonstrated high TUNEL staining indicative of apoptosis. Purkinje cells, identified by the marker calbindin, were severely depleted and, although not TUNEL-positive, displayed strong immunoreactivity for p53, indicating cellular stress. A subset of animals heterozygous for Csb and Xpc deficiencies was more mildly affected, demonstrating ataxia and Purkinje cell loss at 3 months of age. Mouse, Csb(-/-), and Xpc(-/-) embryonic fibroblasts each exhibited increased sensitivity to UV light, which generates bulky DNA damage that is a substrate for excision repair. Whereas Csb(-/-)/Xpc(-/-) fibroblasts were more UV-sensitive than either single knockout, double-heterozygote fibroblasts had normal UV sensitivity. Csb(-/-) mice crossed with a strain defective in base excision repair (Ogg1) demonstrated no enhanced neurodegenerative phenotype. Complete deficiency in nucleotide excision repair therefore renders the brain profoundly sensitive to neurodegeneration in specific cell types of the cerebellum, possibly because of unrepaired endogenous DNA damage that is a substrate for nucleotide but not base excision repair.
机译：Cockayne综合征（CS）是一种罕见的儿童期隐性遗传性神经退行性疾病，其特征是转录偶联核苷酸切除修复的DNA修复途径不足。具有靶向删除CSB基因（Csb（-/-））的小鼠表现出比人类患者更轻的共济失调表型。 Csb（-/-）小鼠也缺乏整体基因组修复功能[Csb（-/-）/ Xerdermadermaosumosum C（Xpc）（-/-）]受更严重的影响，表现出全身消瘦，共济失调和神经衰弱出生后第21天丢失。小脑颗粒细胞显示高TUNEL染色，表明细胞凋亡。由标记calbindin鉴定的浦肯野细胞被严重消耗，尽管不是TUNEL阳性，但显示出对p53的强免疫反应性，表明细胞应激。 Csb和Xpc缺乏的杂合子动物受到的影响较小，表明3个月大时共济失调和Purkinje细胞丢失。小鼠，Csb（-/-）和Xpc（-/-）胚胎成纤维细胞均对紫外线具有更高的敏感性，从而产生庞大的DNA损伤，而DNA损伤是切除修复的基础。 Csb（-/-）/ Xpc（-/-）成纤维细胞比单基因敲除对紫外线更敏感，而双杂合子成纤维细胞对紫外线敏感。 Csb（-/-）小鼠与在基础切除修复（Ogg1）中有缺陷的品系杂交，没有表现出增强的神经变性表型。因此，核苷酸切除修复的完全缺乏使大脑对小脑特定细胞类型的神经退行极为敏感，这可能是由于未修复的内源性DNA损伤是核苷酸的基础，而不是碱基切除修复的基础。

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