PP2A-C 甲基化在锰诱导学习记忆损伤中的作用研究

一碳循环调控蛋白磷酸酶2A催化亚基(PP2A-C)甲基化且对PP2A活性具有重要作用。tau过度磷酸化与学习记忆障碍相关，活化PP2A行使去磷酸化维持tau平衡是神经退行性疾病潜在的治疗靶点。锰可诱导学习记忆损伤，与tau磷酸化异常有关。前期研究发现锰暴露诱导PP2A-C甲基化下降，提示PP2A-C甲基化在锰神经毒性中可能发挥重要作用。根据前期结果及文献推测锰通过干扰一碳代谢循环诱导PP2A-C去甲基化，PP2A活性下降，致tau蛋白磷酸化异常，学习记忆损伤。本研究拟通过细胞实验与动物实验相结合，研究一碳代谢循环调控PP2A-C甲基化在锰诱导的学习记忆损伤中的作用，探讨锰对PP2A-C甲基化调控的方式，并进一步研究调控PP2A-C甲基化水平对锰诱导tau蛋白磷酸化及学习记忆损伤的影响。本研究为深入理解锰神经毒性，有效防治锰诱导的学习记忆损伤及相关神经退行性疾病提供新思路。

The methylation of the C- terminal leucine residue of the PP2A catalytic subunit is important for PP2A catalytic activity, which is regulated by a one-carbon metabolism cycle. Abnormal hyperphosphorylation of tau is strongly associated with learning and memory dysfunction. Activating PP2A to dephosphorylate tau is a potential therapeutic target for neurodegenerative diseases. Excessive manganese exposure induces abnormal tau hyperphosphorylation, which might contribute to learning and memory impairment. Our previous studies show that PP2A-C methylation decreased upon manganese exposure, which implies a crucial role for PP2A-C methylation in manganese neurotoxicity. In view of these results, we presumed that learning and memory impaired by manganese might be due to PP2A catalytic subunit demethylation and loss of its catalytic activity, which leads to tau hyperphosphorylation through one-carbon metabolism disruption. The present study is designed to investigate the regulatory role of PP2A-C methylation through one-carbon metabolism in the mechanism of learning and memory impairment induced by manganese in vivo and vitro. We also discuss the pathways of PP2A-C methylation regulation by manganese and its effects on tau phosphorylation and learning and memory lesion. This study will provide insight into manganese neurotoxicity and new strategies for prevention and treatment of learning and memory damage by manganese or neurodegenerative diseases.