Abstract
Base excision repair (BER) is the major pathway for repair of oxidative DNA damage. Mice with genetic knockout of the BER enzyme Neil3 display compromised neurogenesis in the sub-ventricular zone of the lateral ventricle and sub-granular layer of the dentate gyrus of the hippocampus. To elucidate the impact of oxidative DNA damage-induced neurogenesis on prion disease we applied the experimental prion disease model on Neil3-deficient mice. The incubation period for the disease was similar in both wild type and Neil3−/− mice and the overall neuropathology appeared unaffected by Neil3 function. However, disease in the Neil3−/− mice was of shorter clinical duration. We observed a mildly reduced astrogliosis in the hippocampus and striatum in the Neil3-deficient mice. Brain expression levels of neuronal progenitor markers, nestin (Nestin), sex determining region Box 2 (Sox2), Class III beta-tubulin (Tuj1) decreased towards end-stage prion disease whereas doublecortin (Dcx) levels were less affected. Neuronal nuclei (NeuN), a marker for mature neurons declined during prion disease and more pronounced in the Neil3−/− group. Microglial activation was prominent and appeared unaffected by loss of Neil3. Our data suggest that neurogenesis induced by Neil3 repair of oxidative DNA damage protects against prion disease during the clinical phase.
Highlights
(BER) of reactive oxygen species (ROS)-mediated DNA damage[13]
Neil3-dependent DNA repair appears essential for maintenance of neural stem cell proliferative capacity, which indicates that repair of oxidative DNA damage in neural stem cells (NSC) is required for adult neurogenesis[20]
In order to broaden our understanding of hippocampal neurogenesis during neurodegeneration, we report a study of prion disease in mice with genetic knockout (KO) of Neil[3]
Summary
(BER) of reactive oxygen species (ROS)-mediated DNA damage[13]. The BER pathway is initiated by DNA glycosylases recognizing modified bases[14], including the mammalian NEIL family, where the three members (Neil 1, 2, 3)[13,15,16] are homologous to the E. coli formamidopyrimidine DNA glycosylase and endonuclease VIII (Nei) enzymes[17,18]. The phenotype of mice that are deficient in Neil[3] is associated with impaired proliferative capacity of the neural progenitor cells[19,20]. Neil3-dependent DNA repair appears essential for maintenance of neural stem cell proliferative capacity, which indicates that repair of oxidative DNA damage in NSCs is required for adult neurogenesis[20]. Neil[3] deficient mice showed no change in steady state levels of oxidative DNA damage and genome integrity, indicating a role beyond canonical BER. It appears that Neil[3] deficient mice are an interesting model for studying the impact of impaired neurogenesis in neurodegenerative disease. In order to broaden our understanding of hippocampal neurogenesis during neurodegeneration, we report a study of prion disease in mice with genetic knockout (KO) of Neil[3]
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