Neurovascular dysfunction in a mouse model of Cockayne syndrome

Abstract

Cockayne Syndrome (CS) is a rare, autosomal genetic disorder characterized by premature aging-like features, such as cachetic dwarfism, early cell senescence and progressive neurodegeneration, characterized by patchy demyelination, brain atrophy, and hearing loss. The underlying genetic defect in CS lies in genes associated with the transcription-coupled arm of the nucleotide excision DNA repair (NER) pathway, although how defective DNA repair leads to the particular symptoms of CS is not clear. A mouse model of severe CS with total loss of NER, termed the CX model, recapitulates CS-related progressive neurodegeneration resulting in death at approximately 20 weeks of age. CX and related mouse models also presents with vascular defects, including hardening of the arteries and pro-inflammatory responses. We hypothesize that neurovascular dysfunction/inflammation could thus contribute to the progressive neurodegeneration observed in this model as well as the human disease. Published and ongoing studies in the Mitchell lab have identified interventions that extend lifespan of the short-lived CX mouse model, and may thus impact progressive neurodegeneration that is the cause of early mortiality. Two such interventions, dietary methionine restriction (MR) and pharmacological NAD+ supplementation appear to work in parallel to improve vascular health through increased angiogenesis. MR does this by increasing endogenous production of the pro-angiogenic gas, hydrogen sulfide, while the metabolic cofactor NAD+ activates the NAD-dependent deacetylase SIRT1, which is required for angiogenesis. The first goal of the project is to characterize vascular dysfunction and its association with neuroinflammation and degeneration using existing cross-sectional tissues harvested from CX mice. The second goal of the project is to test the ability of H2S and NAD+ supplementation together to improve vascular function, reduce neuroinflammation and extend longevity.We expect that the results obtained during this project will help to elucidate the underlying mechanisms of CS pathology, while also studying possible therapies for the neurodegenerative phenotype of this yet untreatable disorder. (AU)