The role of the Cockayne syndrome protein

柯凯因综合征（CS）是一种毁灭性的常染色体隐性遗传病，以神经变性、恶病质和加速衰老为特征。80%的病例是由已知参与DNA修复和转录的CS互补组B （CSB）基因突变引起的。在CS细胞中，细胞核和线粒体DNA中氧化DNA损伤的修复存在缺陷，这可能是该疾病的主要潜在原因。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，并且这两种蛋白在细胞对氧化应激的反应中合作。PARP1代谢NAD+，因此，在靶组织如大脑中，低水平的NAD+可能导致CS病理，包括其严重的早发性神经变性。

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.