Methionine-Mediated Protein Phosphatase 2A Catalytic Subunit (PP2Ac) Methylation Ameliorates the Tauopathy Induced by Manganese in Cell and Animal Models
Methionine-Mediated Protein Phosphatase 2A Catalytic Subunit (PP2Ac) Methylation Ameliorates the Tauopathy Induced by Manganese in Cell and Animal Models
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DOI：
10.1007/s13311-020-00930-6
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发表时间：
2020-09
影响因子：
5.7
通讯作者：
Bin Wu;Haiqing Cai;Shen Tang;Yilu Xu;Qianqian Shi;Lancheng Wei;L. Meng;Ning Zhang;Xinhang Wang;Deqiang Xiao;Yunfeng Zou;Xiaobo Yang;Xiyi Li;Cailing Lu
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作者：
Bin Wu;Haiqing Cai;Shen Tang;Yilu Xu;Qianqian Shi;Lancheng Wei;L. Meng;Ning Zhang;Xinhang Wang;Deqiang Xiao;Yunfeng Zou;Xiaobo Yang;Xiyi Li;Cailing Lu
锰（Mn）暴露诱导的阿尔茨海默样认知障碍的分子机制尚未完全阐明，并且目前没有有效的干预措施来治疗与锰中毒相关的神经退行性病变。蛋白磷酸酶2A（PP 2A）是一种主要的tau蛋白磷酸酶，最近被鉴定为神经退行性疾病的潜在治疗靶分子;其活性由催化C亚基的甲基化状态指导。蛋氨酸是一种必需氨基酸，其下游代谢产物S-腺苷甲硫氨酸（SAM）作为甲基供体参与转甲基途径。本研究在锰暴露的细胞模型和大鼠模型中，评价了锰的神经毒性机制和蛋氨酸的保护作用。我们发现，锰诱导的神经毒性的特征是PP 2Ac去甲基化伴随着异常降低LCMT-1和增加PME-1，这与tau蛋白过度磷酸化和空间学习记忆障碍，并在海马SAM的可用性差，可能是决定损失的PP 2Ac甲基化。重要的是，通过连续补充外源性甲硫氨酸或通过体外给予ABL 127特异性抑制PP 2Ac去甲基化来维持局部SAM水平，可以有效地防止tau过度磷酸化，从而减少细胞或动物Mn暴露模型中的细胞氧化应激、凋亡、细胞活力损伤和大鼠记忆缺陷。总之，我们的数据表明，SAM和PP 2Ac甲基化可能是治疗锰中毒和神经毒性机制相关的tau蛋白病的新靶点。
The molecular mechanism of Alzheimer-like cognitive impairment induced by manganese (Mn) exposure has not yet been fully clarified, and there are currently no effective interventions to treat neurodegenerative lesions related to manganism. Protein phosphatase 2 A (PP2A) is a major tau phosphatase and was recently identified as a potential therapeutic target molecule for neurodegenerative diseases; its activity is directed by the methylation status of the catalytic C subunit. Methionine is an essential amino acid, and its downstream metabolite S-adenosylmethionine (SAM) participates in transmethylation pathways as a methyl donor. In this study, the neurotoxic mechanism of Mn and the protective effect of methionine were evaluated in Mn-exposed cell and rat models. We show that Mn-induced neurotoxicity is characterized by PP2Ac demethylation accompanied by abnormally decreased LCMT-1 and increased PME-1, which are associated with tau hyperphosphorylation and spatial learning and memory deficits, and that the poor availability of SAM in the hippocampus is likely to determine the loss of PP2Ac methylation. Importantly, maintenance of local SAM levels through continuous supplementation with exogenous methionine, or through specific inhibition of PP2Ac demethylation by ABL127 administration in vitro, can effectively prevent tau hyperphosphorylation to reduce cellular oxidative stress, apoptosis, damage to cell viability, and rat memory deficits in cell or animal Mn exposure models. In conclusion, our data suggest that SAM and PP2Ac methylation may be novel targets for the treatment of Mn poisoning and neurotoxic mechanism-related tauopathies.