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

N. Haruyama, Sakumi Kunihiko, Atsuhisa Katogi, Daisuke Tsuchimoto, Gabriele De Luca, Margherita Bignami, Yusaku Nakabeppu

Research output: Contribution to journalArticle

Abstract

In mammals, including humans, MTH1 with 8-oxo-dGTPase and OGG1 with 8-oxoguanine DNA glycosylase minimize 8-oxoguanine accumulation in genomic DNA. We investigated age-related alterations in behavior, 8-oxoguanine levels, and neurogenesis in the brains of Mth1/Ogg1-double knockout (TO-DKO), Ogg1-knockout, and human MTH1-transgenic (hMTH1-Tg) mice. Spontaneous locomotor activity was significantly decreased in wild-type mice with age, and females consistently exhibited higher locomotor activity than males. This decrease was significantly suppressed in female but not male TO-DKO mice and markedly enhanced in female hMTH1-Tg mice. Long-term memory retrieval was impaired in middle-aged female TO-DKO mice. 8-Oxoguanine accumulation significantly increased in nuclear DNA, particularly in the dentate gyrus (DG), subventricular zone (SVZ) and major island of Calleja (ICjM) in middle-aged female TO-DKO mice. In middle-aged female TO-DKO mice, neurogenesis was severely impaired in SVZ and DG, accompanied by ICjM and DG atrophy. Conversely, expression of hMTH1 efficiently suppressed 8-oxoguanine accumulation in both SVZ and DG with hypertrophy of ICjM. These findings indicate that newborn neurons from SVZ maintain ICjM in the adult brain, and increased accumulation of 8-oxoguanine in nuclear DNA of neural progenitors in females is caused by 8-oxo-dGTP incorporation during proliferation, causing depletion of neural progenitors, altered behavior, and cognitive function changes with age.

Original languageEnglish
Article number101613
JournalProgress in Neurobiology
Volume180
DOIs
Publication statusPublished - Sep 1 2019

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Islands of Calleja
Neurogenesis
Dentate Gyrus
Phenotype
Lateral Ventricles
Brain
Locomotion
Transgenic Mice
DNA
DNA Glycosylases
Long-Term Memory
8-hydroxyguanine
Cognition
Hypertrophy
Atrophy
Mammals
Neurons

All Science Journal Classification (ASJC) codes

  • Neuroscience(all)

Cite this

8-Oxoguanine accumulation in aged female brain impairs neurogenesis in the dentate gyrus and major island of Calleja, causing sexually dimorphic phenotypes. / Haruyama, N.; Kunihiko, Sakumi; Katogi, Atsuhisa; Tsuchimoto, Daisuke; De Luca, Gabriele; Bignami, Margherita; Nakabeppu, Yusaku.

In: Progress in Neurobiology, Vol. 180, 101613, 01.09.2019.

Research output: Contribution to journalArticle

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