Cockayne syndrome proteins CSA and CSB maintain mitochondrial homeostasis through NAD+ signaling [HumanHT-12 V4.0]

Cockayne syndrome (CS) is a rare premature aging disease, which in the majority of cases is caused by mutations of the genes encoding the CSA or CSB proteins. CS patients display cachectic dwarfism and severe neurological manifestations and die by 12 years of age on average. The CS proteins are involved in transcription and DNA repair, including a specialized form of DNA repair called transcription-coupled nucleotide excision repair (TC-NER). However, there is also evidence for mitochondrial dysfunction in CS, likely contributing to the severe premature aging phenotype of this disease. Our cross-species transciptomic analysis in CS postmortem brain tissue, CS mouse and C. elegans models showed that mitochondrial dysfunction is indeed a common feature in CS. Interestingly, the restoration of mitochondrial dysfunction through NAD+ supplementation significantly improved lifespan and healthspan in the C. elegans models of CS, highlighting mitochondrial dysfunction as a major driver of the aging features of CS. We proceeded to perform molecular studies on cerebellar samples obtained from CS patients. We found that these patients exhibited molecular signatures of dysfunctional mitochondrial dynamics that can be corrected with NAD+ supplementation in primary cells with depleted CSA or CSB. Our study provides support for the interconnection between two major aging theories, DNA damage and mitochondrial dysfunction. Together these two agents contribute to an accelerated aging program that can be averted by NAD+ supplementation. Postmortem samples of Cockayne syndrome (CS, N = 7) and control (WT, N=5) cerebellum was obtained from the NIH NeuroBioBank’s Brain and Tissue repository at the University of Maryland, Baltimore.