Gunn A. Hildrestrand

Oxidative DNA damage in the brain has been implicated in neurodegeneration and cognitive decline. DNA glycosylases initiate base excision repair (BER), the main pathway for oxidative DNA base lesion repair. NEIL1 and NEIL3 DNA glycosylases affect cognition in mice, while the role of NEIL2 remains unclear. Here, we investigate the impact of NEIL2 and its potential overlap with NEIL1 on behavior in knockout mouse models. Neil1^−/−Neil2^−/− mice display hyperactivity, reduced anxiety and improved learning. Hippocampal oxidative DNA base lesion levels are comparable between genotypes and no mutator phenotype is found. Thus, impaired canonical repair is not likely to explain the altered behavior. Electrophysiology suggests reduced axonal activation in the hippocampal CA1 region in Neil1^−/−Neil2^−/− mice and lack of NEIL1 and NEIL2 causes dysregulation of genes in CA1 relevant for synaptic function. We postulate a cooperative function of NEIL1 and NEIL2 in genome regulation, beyond canonical BER, modulating behavior in mice.

The human brain requires a high rate of oxygen consumption to perform intense metabolic activities, accounting for 20% of total body oxygen consumption. This high oxygen uptake results in the generation of free radicals, including reactive oxygen species (ROS), which, at physiological levels, are beneficial to the proper functioning of fundamental cellular processes. At supraphysiological levels, however, ROS and associated lesions cause detrimental effects in brain cells, commonly observed in several neurodegenerative disorders. In this review, we focus on the impact of oxidative DNA base lesions and the role of DNA glycosylase enzymes repairing these lesions on brain function and disease. Furthermore, we discuss the role of DNA base oxidation as an epigenetic mechanism involved in brain diseases, as well as potential roles of DNA glycosylases in different epigenetic contexts. We provide a detailed overview of the impact of DNA glycosylases on brain metabolism, cognition, inflammation, tissue loss and regeneration, and age-related neurodegenerative diseases based on evidence collected from animal and human models lacking these enzymes, as well as post-mortem studies on patients with neurological disorders.

Increasing evidence suggests that oxidative DNA damage accumulates in atherosclerosis. Recently, we showed that a genetic variant in the human DNA repair enzyme NEIL3 was associated with increased risk of myocardial infarction. Here, we explored the role of Neil3/NEIL3 in atherogenesis by both clinical and experimental approaches. Human carotid plaques revealed increased NEIL3 mRNA expression which significantly correlated with mRNA levels of the macrophage marker CD68. Apoe^−/−Neil3^−/− mice on high-fat diet showed accelerated plaque formation as compared to Apoe^−/− mice, reflecting an atherogenic lipid profile, increased hepatic triglyceride levels and attenuated macrophage cholesterol efflux capacity. Apoe^−/−Neil3^−/− mice showed marked alterations in several pathways affecting hepatic lipid metabolism, but no genotypic alterations in genome integrity or genome-wide accumulation of oxidative DNA damage. These results suggest a novel role for the DNA glycosylase Neil3 in atherogenesis in balancing lipid metabolism and macrophage function, potentially independently of genome-wide canonical base excision repair of oxidative DNA damage.

The base excision repair pathway is responsible for repairing small DNA base lesions caused by endogenous and exogenous damaging agents. Repair is initiated by DNA glycosylases that recognize and remove the lesions. NEIL3 is one of 11 mammalian DNA glycosylases identified to date and it was discovered on the basis of sequence homology to the E. coli Fpg and Nei glycosylases. Difficulties in purifying the protein have limited its biochemical characterization and in contrast to the other glycosylases, its function remains unclear.