Methionine-Mediated Protein Phosphatase 2A Catalytic Subunit (PP2Ac) Methylation Ameliorates the Tauopathy Induced by Ma
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ORIGINAL ARTICLE
Methionine-Mediated Protein Phosphatase 2A Catalytic Subunit (PP2Ac) Methylation Ameliorates the Tauopathy Induced by Manganese in Cell and Animal Models Bin Wu 1,2 & Haiqing Cai 1,2 & Shen Tang 3 & Yilu Xu 1,2 & Qianqian Shi 1,2 & Lancheng Wei 1,2 & Ling Meng 3 & Ning Zhang 1,2 & Xinhang Wang 3 & Deqiang Xiao 1,2 & Yunfeng Zou 1,2 & Xiaobo Yang 1,2 & Xiyi Li 1,2 & Cailing Lu 1,2 Accepted: 4 September 2020 # The American Society for Experimental NeuroTherapeutics, Inc. 2020
Abstract 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. Key Words Methionine . ABL127 . manganism . tau . neurodegeneration . PP2Ac methylation
Introduction Bin Wu, Haiqing Cai and Shen Tang contributed equally to this work. * Xiyi Li [email protected] * Cailing Lu [email protected] 1
School of Public Health, Guangxi Medical University, 22 Shuangyong Road, Nanning 530021, Guangxi, People’s Republic of China
2
Guangxi Colleges and Universities Key Laboratory of Prevention and Control of Highly Prevalent Diseases, Guangxi Medical University, 22 Shuangyong Road, Nanning 530021, Guangxi, People’s Republic of China
3
School of Basic Medical Sciences, Guangxi Medical University, 22 Shuangyong Road, Nanning 530021, Guangxi, People’s Republic of China
Although manganese (Mn) is an essential trace metal to maintain the homeostasis of the nervous system in mammalian animals [1, 2], overexposure to Mn from occupational settings and t
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