Wang Xiao-Ling, Wei Xin, Yuan Jing-Jing, Mao Yuan-Yuan, Wang Zhong-Yu, Xing Na, Gu Han-Wen, Lin Cai-Hong, Wang Wen-Ting, Zhang Wei, Xing Fei
Department of Anesthesiology, Pain and Perioperative Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
Henan Province International Joint Laboratory of Pain, Cognition and Emotion, Zhengzhou, China.
Front Cell Neurosci. 2022 May 12;16:884296. doi: 10.3389/fncel.2022.884296. eCollection 2022.
N6-methyladenosine (mA) is the most abundant methylation modification on mRNA in mammals. Fat mass and obesity-related protein (FTO) is the main RNA mA demethylase. FTO is involved in the occurrence and maintenance of neuropathic pain (NP). NP often induces mental disorders. We found that NP downregulated the expression of FTO in the anterior cingulate cortex (ACC), inhibited the expression of matrix metalloproteinase-9 (MMP-9) in the ACC, maladjusted the brain-derived neurotrophic factor precursor (proBDNF) and mature brain-derived neurotrophic factor (mBDNF) levels in the ACC, and induced anxiety- and depression-like behaviors in mice. Blocking the downregulation of FTO in the ACC induced by peripheral nerve injury could reverse the anxiety- and depression-like behaviors of mice. Contrarily, downregulation of simulated FTO induced anxiety- and depression-like behaviors in mice. After peripheral nerve injury, the binding of FTO to MMP-9 mRNA decreased and the enrichment of mA on MMP-9 mRNA increased. In conclusion, downregulation of FTO in ACC by regulating MMP-9 mRNA methylation level contributes to the occurrence of anxiety- and depression-like behaviors in NP mice.
N6-甲基腺苷（mA）是哺乳动物mRNA上最丰富的甲基化修饰。脂肪量和肥胖相关蛋白（FTO）是主要的RNA mA去甲基化酶。FTO参与神经性疼痛（NP）的发生和维持。NP常诱发精神障碍。我们发现，NP下调前扣带回皮质（ACC）中FTO的表达，抑制ACC中基质金属蛋白酶9（MMP-9）的表达，使ACC中脑源性神经营养因子前体（proBDNF）和成熟脑源性神经营养因子（mBDNF）水平失调，并诱导小鼠出现焦虑和抑郁样行为。阻断外周神经损伤诱导的ACC中FTO的下调可逆转小鼠的焦虑和抑郁样行为。相反，模拟下调FTO可诱导小鼠出现焦虑和抑郁样行为。外周神经损伤后，FTO与MMP-9 mRNA的结合减少，MMP-9 mRNA上mA的富集增加。总之，通过调节MMP-9 mRNA甲基化水平下调ACC中的FTO有助于NP小鼠出现焦虑和抑郁样行为。
