Alterations in Energy Metabolism and Neurodegeneration as a Conseqeunce of DNA Damage
Brace, Lear Elizabeth
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AbstractThe correlation between DNA damage and aging has been discussed since Peter Medawar framed the first modern theory of aging in 1952. In support of a causal relationship between DNA damage and aging, most human segmental progeroid disorders, which share some but not all of the characteristics of aging, are associated with defects in DNA damage repair and signaling processes. One such example is Cockayne syndrome (CS), which is characterized by neurodegeneration, cerebellar ataxia and failure to thrive, caused by inborn defects in key proteins of the transcription-coupled arm of the nucleotide excision DNA repair pathway (NER). Here, we created a new mouse model of CS by combining two different null alleles in the NER pathway. Double homozygous mutant Csa|Xpa, or CX mice, represent the first mouse model of severe CS that survive the weaning period with high penetrance, solving a recurring problem with previous models. After weaning, CX mice present with progressive loss of adiposity and neurodegenerative complications that accurately mimic the human disease. Investigations into adiposity loss revealed that oxidative phosphorylation, specifically fatty acid oxidation (FAO), is significantly increased upon the chronic accumulation of DNA damage in CX animals in vivo and in vitro, and also in CS patient cell lines. The increase in FAO is dependent on PARP-1 activation, driving NAD+/ATP depletion and subsequent activation of AMPK, increasing FAO-related gene expression. We further demonstrate that increased FAO is a general response to DNA damage, as acute doses of numerous genotoxic agents similarly increased fat burning in wildtype mice both in vitro and in vivo. This metabolic adaptation is also beneficial, as blocking FAO reduced cell viability upon damage and increasing FAO further extended the lifespan of CX mice via a diet reduced in methionine. Investigations of the role of myelin loss in neurodegeneration of CX mice were also performed. Age-dependent loss of myelin, astrogliosis, and increased mRNA expression of enzymes that act to catabolize myelin lipids were observed in CX brains compared to controls. Increased FAO capacity was also observed in CX brain and sciatic nerve, with cultured primary astrocytes of the CX central nervous system identified as the likely cell type responsible for this fat burning. Whether increased FAO by astrocytes contributes to the patchy loss of white matter/myelin in CX nervous tissue and subsequent neurodegeneration remains an outstanding issue. Lastly, we utilized CX mice to analyze potential new endpoints, such as hematopoietic cell growth, circulating liver enzyme levels, and adipocyte dysfunction, as markers of therapeutic interventional efficacy of pharmacological approaches including NAD+ supplementation. The CX mouse model thus represents a valuable tool that accurately models important aspects of human Cockayne syndrome, and may also be used to shed light on the role of DNA damage in physiological aging.
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