The role of the Cockayne syndrome protein

National Institute On Aging

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Abstract

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.