Accumulation of major oxidized base among the nucleotide pool in the aged brain

Title: 8-Oxoguanine accumulation in aged female brain impairs neurogenesis in the dentate gyrus and major island of Calleja, causing sexually dimorphic phenotypes

Journal: Progress in Neurobiology 180 (2019) 101613

Link: https://doi.org/10.1016/j.pneurobio.2019.04.002

Comments:

Guanine is a nucleobase most susceptible to oxidation. Upon oxidation, it is modified to 8-oxo-guanine accumulated in the brain with neurodegenerative disorders such as Alzheimer disease.

Current study focused on two enzymes Mth1 and Ogg1. Mth1 hydrolyzes 8-oxo-2’-deoxygianosine triphosphate and avoid incorporation of it into intracellular space, while Ogg1 eliminate 8-oxo-guanine with initiating base excision repair.

Adult neurogenesis is peculiar in that it underlies neural plasticity as a basis of cognitive functions such as memory formation and retrieval. A limited number of brain regions are known to exhibit such activity including dentate gyrus and subventricular zone. Analysis revealed that Mth1/Ogg1 double knockout mice showed impairment in long-term memory retrieval in Morris water maze test. Interestingly, this phenotype was observed only in the aged female mice. In accordance with this finding, the authors observed 8-oxogianine accumulated in the nuclei of immature neurons in those areas with adult neurogenesis, which might account for the reduced neurogenesis and cognitive impairment.

Specific phenotype in female may be attributed to a role of female sex hormone estrogen. The authors discussed a possible contribution of estrogen to the modulation of reactive oxygen species production. Histone lysine demethylases (LSD1) activated by the persistent estrogen might underlie it, since LSD1 is known to catalyze demethylation of amine oxidase, which lead to the production of hydrogen peroxide.