Canugovi Chandrika, Misiak Magdalena, Scheibye-Knudsen Morten, Croteau Deborah L, Mattson Mark P, Bohr Vilhelm A
Laboratory of Molecular Gerontology, National Institute on Aging, National Institutes of Health, Baltimore, MD, USA.
Laboratory of Molecular Gerontology, National Institute on Aging, National Institutes of Health, Baltimore, MD, USA; Laboratory of Neurosciences, National Institute on Aging, National Institutes of Health, Baltimore, MD, USA.
Neurobiol Aging. 2015 Feb;36(2):1007-12. doi: 10.1016/j.neurobiolaging.2014.09.026. Epub 2014 Oct 14.
Oxidative DNA damage accumulation has been implicated in neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease. The base excision repair pathway is a primary responder to oxidative DNA damage. Effects of loss of base excision repair on normal brain function is a relatively nascent area of research that needs further exploration for better understanding of related brain diseases. Recently, we found that loss of a versatile DNA glycosylase endonuclease 8-like 1 (NEIL1) causes deficits in spatial memory retention using the Morris water maze test. Furthermore, we found that there is a significant loss of NEIL1 enzyme levels and its activity in postmortem Alzheimer's disease brains. Based on the Allen Brain Atlas in situ hybridization data, the expression levels of Neil1 messenger RNA are higher in the olfactory bulb compared with other areas of the brain. Olfaction in mice is a central brain function that involves many central nervous system pathways. Here, we studied the effect of complete loss of Neil1 gene on olfactory function. We explored olfactory function in mice with 3 different behavioral tests namely, olfactory sensitivity, performance, and buried food tests. Neil1(-/-) mice performed poorly compared with wild-type mice in all 3 tests. Our data indicate that loss of Neil1 causes olfactory function deficits supporting our previous findings and that normal brain function requires robust DNA repair.
氧化DNA损伤的积累与神经退行性疾病如阿尔茨海默病和帕金森病有关。碱基切除修复途径是对氧化DNA损伤的主要应答者。碱基切除修复缺失对正常脑功能的影响是一个相对新兴的研究领域，需要进一步探索以更好地理解相关脑部疾病。最近，我们发现使用莫里斯水迷宫试验，多功能DNA糖基化酶内切酶8样1（NEIL1）的缺失会导致空间记忆保持能力的缺陷。此外，我们发现在阿尔茨海默病死后大脑中，NEIL1酶水平及其活性显著丧失。基于艾伦脑图谱原位杂交数据，与大脑其他区域相比，嗅球中Neil1信使RNA的表达水平更高。小鼠的嗅觉是一种涉及许多中枢神经系统途径的中枢脑功能。在这里，我们研究了Neil1基因完全缺失对嗅觉功能的影响。我们通过3种不同的行为测试，即嗅觉敏感性、行为表现和埋藏食物测试，探索了小鼠的嗅觉功能。在所有3项测试中，Neil1（-/-）小鼠的表现均不如野生型小鼠。我们的数据表明，Neil1的缺失会导致嗅觉功能缺陷，这支持了我们之前的发现，即正常脑功能需要强大的DNA修复。
