Neil3 induced neurogenesis protects against prion disease during the clinical phase

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.

Oxidative stress and DNA damage after cerebral ischemia: Potential therapeutic targets to repair the genome and improve stroke recovery

“…NEIL3 deficiency in cultured neural stem/progenitor cells significantly impairs the repair of oxidative DNA base lesions (Sejersted et al, 2011). NEIL3 also promotes neurogenesis and protects against prion disease by reducing oxidative DNA damage (Jalland et al, 2016). Although it is still unknown whether DNA repair can promote neurogenesis after stroke, DNA integrity appears to be crucial for neuron survival in humans; the acute stage of human stroke is characterized by DNA fragmentation and repair in cortical neurons, whereas the chronic stage of stroke is associated with DNA integrity, supporting the clinical importance of genomic integrity for long term viability after stroke (Huttner et al, 2014).…”

“…Recent studies highlight the important role of DNA repair as a critical element of the endogenous brain repair process during stroke recovery (Li et al, 2006; Liu et al, 2011). DNA repair has a profound impact on a wide range of recovery efforts, including neurogenesis (Jalland et al, 2016; Shimada et al, 2015), angiogenesis (Liu et al, 2015b), axonal outgrowth (Liu et al, 2015a), and remyelination (Stetler et al, 2016), all of which work in concert to orchestrate neurological recovery. Targeting DNA damage and endogenous DNA repair mechanisms after stroke holds promise for accelerating brain tissue repair and functional recovery.…”

A role for the base excision repair enzyme NEIL3 in replication-dependent repair of interstrand DNA cross-links derived from psoralen and abasic sites

“…It is also interesting to note that Neil3 − / − knockout mice have been generated [134, 135]. These mice do not display a profound phenotype, although loss of proliferating neuronal progenitors was noted after hypoxia-ischemia, leading to the suggestion that “NEIL3 exercises a highly specialized function through accurate molecular repair of DNA in rapidly proliferating cells” [134].…”

Microphysiological stroke model for systematic evaluation of neurorestorative potential of stem cell therapy

“…Microglia are the resident macrophages and the only immune cell type in the brain 66 . Due to the issues of reliable batch-to-batch reproducibility with human primary microglia, we used a transformed human microglial cell line (HMC3, ATCC).…”