The DNA repair-ubiquitin-associated HR23 proteins are constituents of neuronal inclusions in specific neurodegenerative disorders without hampering DNA repair
The DNA repair-ubiquitin-associated HR23 proteins are constituents of neuronal inclusions in specific neurodegenerative disorders without hampering DNA repair
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DOI：
10.1016/j.nbd.2006.06.005
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发表时间：
2006-09-01
影响因子：
6.1
通讯作者：
Willemsen, Rob
中科院分区：
文献类型：
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作者：
Bergink, Steven;Severijnen, Lies-Anne;Willemsen, Rob
细胞内包涵体在许多神经退行性疾病中起着重要作用。在这里，我们报告了HR 23 B和HR 23 A，参与DNA修复和穿梭蛋白质到26 S蛋白酶体进行降解的蛋白质，在FXTAS小鼠模型的脑神经元包涵体中积累，以及在HD，SCA 3，SCA 7，FTDP-17和PD患者的脑材料中积累。有趣的是，HR 23 B在AD患者的tau阳性聚集体（神经元缠结）中没有显著积累，而泛素则有。HR 23蛋白在细胞内包涵体中的隔离不会导致其在DNA修复中的稳定结合伴侣XPC的可检测积累。令人惊讶的是，在过表达GFP-polyQ的原代人成纤维细胞中没有观察到修复能力的降低，GFP-polyQ是一种在这些转染的细胞中诱导HR 23 B阳性包涵体的多肽。这说明扩展的谷氨酰胺重复序列对泛素-蛋白酶体系统（UPS）的损害，包括HR 23 B的螯合，不影响NER。(c)2006爱思唯尔公司All rights reserved.
Intracellular inclusions play a profound role in many neurodegenerative diseases. Here, we report that HR23B and HR23A, proteins that are involved in both DNA repair and shuttling proteins to the 26S proteasome for degradation, accumulate in neuronal inclusions in brain from a mouse model for FXTAS, as well as in brain material from HD, SCA3, SCA7, FTDP-17 and PD patients. Interestingly, HR23B did not significantly accumulate in tau-positive aggregates (neurofibrillary tangles) from AD patients while ubiquitin did. The sequestration of HR23 proteins in intracellular inclusions did not cause detectable accumulation of their stable binding partner in DNA repair, XPC. Surprisingly, no reduction in repair capacity was observed in primary human fibroblasts that overexpressed GFP-polyQ, a polypeptide that induces HR23B-positive inclusions in these transfected cells. This illustrates that impairment of the ubiquitin-proteasome system (UPS) by expanded glutamine repeats, including the sequestration of HR23B, is not affecting NER. (c) 2006 Elsevier Inc. All rights reserved.