The role of the Cockayne syndrome protein

Cockayne综合征(CS)是一种以神经变性、恶病质和加速衰老为特征的常染色体隐性遗传病。80%的病例是由CS互补B组(CSB)基因突变引起的，已知的CSB基因涉及DNA修复和转录。在CS细胞中，核和线粒体DNA氧化损伤的修复存在缺陷，这可能是该病的主要潜在原因。在此之前，我们证明了CSB蛋白与PARP1蛋白相互作用，PARP1蛋白参与DNA单链断裂修复的早期步骤，这两种蛋白在细胞对氧化应激的反应中相互作用。PARP1代谢NAD+，因此，在像大脑这样的靶组织中，较低水平的NAD+可能是CS病理包括严重的早发性神经变性的原因之一。 携带CSB突变的小鼠的临床表现包括听力损失、小胶质细胞激活、恶病质，与人类患者中灾难性的CS疾病表型相比轻微。我们最近的研究揭示了CSB小鼠模型的新特征，包括代谢率升高和自噬改变。在CSB缺陷的细胞中，线粒体含量增加，而自噬下调。CSB小鼠非常瘦，所以我们测试了改变饮食是否会有好处。CSB小鼠给予高脂肪或热量限制的饮食，高脂肪饮食是有益的。然而，相比之下，限制卡路里的饮食加剧了CSB小鼠的特征。这些发现引导我们提出，CS的某些特征可能适用于针对线粒体健康的干预，未来的研究正在进行中，以探索可能对CSB患者有益的营养选择。 未来的研究正在进行中，以询问为什么CsA和CSB的缺失都会导致相同的疾病，而蛋白质却如此不同。CsA和CSB缺乏的多种生物体正在被用来更准确地定义什么统一性状是导致过早老化的CS表型的原因。广泛的表达阵列分析表明，CsA和CSB蛋白有许多共同的途径，正在探索这些途径，以期更准确地确定这两种蛋白质的共同作用点。

Cockayne syndrome (CS) is a devastating autosomal recessive disease characterized by neurodegeneration, cachexia, and accelerated aging. 80% of the cases are caused by mutations in the CS complementation group B (CSB) gene known to be involved in DNA repair and transcription. In CS cells, there are deficiencies in the repair of oxidative DNA damage in nuclear and mitochondrial DNA, and this may be a major underlying cause of the disease. Previously, we demonstrated that the CSB protein interacts with PARP1, a protein involved in the early steps of DNA single-strand break repair, and that these two proteins cooperate in the cellular responses to oxidative stress. PARP1 metabolizes NAD+, and consequently, in target tissues like the brain, lower levels of NAD+ may be contributing to CS pathology including its severe early onset neurodegeneration. The clinical presentation of mice carrying a mutation in CSB involves hearing loss, microglial activation, cachexia, and are mild compared to the catastrophic disease phenotype of CS in human patients. Our recent studies revealed novel features in the Csb mouse model, including elevated metabolic rate and altered autophagy. Mitochondrial content is increased in CSB-deficient cells, whereas autophagy is down-regulated. Csb mice are very lean so we tested whether an altered diet may be of benefit. A high fat or caloric restricted diet was delivered to the Csb mice and the high fat diet was of benefit. However, in contrast, a caloric restrictive diet exacerbated the features of the Csb mouse. These findings lead us to propose that some features of CS may be amenable to interventions that target mitochondrial health and future research is underway to explore nutraceutical options that may have benefit for CSB patients. Moving forward studies are underway to interrogate why loss of CSA and CSB each cause the same disorder yet the proteins are so different. Multiple organisms deficient in CSA and CSB are being employed to define more precisely what unifying trait is responsible for the premature aging CS phenotypes. Extensive expression array analysis suggests that CSA and CSB protein share a number of common pathways and these are being explored with a view to pinpoint more precisely the common point of action of these two proteins.