Division of Neurofunctional Genomics, Department of Immunobiology and Neuroscience, Medical Institute of Bioregulation, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan; Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.
Division of Neurofunctional Genomics, Department of Immunobiology and Neuroscience, Medical Institute of Bioregulation, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.
Prog Neurobiol. 2019 Sep;180:101613. doi: 10.1016/j.pneurobio.2019.04.002. Epub 2019 Apr 23.
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.
在包括人类在内的哺乳动物中，MTH1 具有 8-氧代-dGTP 酶活性，OGG1 具有 8-氧鸟嘌呤 DNA 糖基化酶活性，可最大限度地减少基因组 DNA 中 8-氧鸟嘌呤的积累。我们研究了 Mth1/Ogg1 双敲除（TO-DKO）、Ogg1 敲除和人 MTH1 转基因（hMTH1-Tg）小鼠大脑中与年龄相关的行为、8-氧鸟嘌呤水平和神经发生的变化。自发运动活性随年龄的增长而显著下降，且雌性的运动活性始终高于雄性。这种下降在雌性 TO-DKO 小鼠中显著受到抑制，而在雄性中则明显增强，在雌性 hMTH1-Tg 小鼠中更为显著。中年雌性 TO-DKO 小鼠的长时记忆检索受损。8-氧鸟嘌呤在核 DNA 中的积累显著增加，特别是在齿状回（DG）、侧脑室下区（SVZ）和主要卡列加岛（ICjM）中。在中年雌性 TO-DKO 小鼠中，SVZ 和 DG 中的神经发生严重受损，同时伴有 ICjM 和 DG 萎缩。相反，hMTH1 的表达有效地抑制了 SVZ 和 DG 中 8-氧鸟嘌呤的积累，同时使 ICjM 肥大。这些发现表明，SVZ 中的新生神经元维持成年大脑中的 ICjM，并且女性神经祖细胞核 DNA 中 8-氧代-dGTP 的积累增加是由于增殖过程中 8-氧代-dGTP 的掺入导致神经祖细胞耗竭，导致行为改变和认知功能随年龄变化。
