Li Zhengyu, Chen Xin, Xiang Wenwen, Tang Ting, Gan Li
Department of Neurology, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang 330006, Jiangxi Province, P.R. China.
ACS Chem Neurosci. 2025 Feb 5;16(3):405-416. doi: 10.1021/acschemneuro.4c00620. Epub 2025 Jan 23.
: Parkinson's disease (PD) is a neurodegenerative disorder characterized by the involvement of ferroptosis in its pathological mechanism. In this study, the effects and mechanism of BRCA1-associated protein 1 (BAP1) on neuronal ferroptosis in PD were evaluated. : A PD mouse model was constructed by injecting mice with MPTP. Nissl staining, immunohistochemistry, immunofluorescence, and Prussian blue staining evaluated histopathology and iron distribution. The PD cell model was constructed by subjecting SK-N-SH cells to MPP. The m6A level of BAP1 was assessed by MeRIP. mRNA levels of BAP1, FTO, IGF2BP1, METTL3, YTHDF2, and SLC7A11 were evaluated utilizing RT-qPCR. Protein levels of BAP1, FTO, IGF2BP1, METTL3, YTHDF2, SLC7A11, and p53 were measured by Western blot. Cell viability was assessed using CCK-8 assay, and TUNEL was used for assessing apoptosis. The levels of MDA, GSH, SOD, and Fe were also measured. The interactions among molecules were verified using RIP assay, dual luciferase reporter assay, and ChIP assay. : SK-N-SH cells treated with MPP showed a decrease in overall m6A levels of BAP1. FTO facilitated m6A demethylation of BAP1, leading to an increased level of expression of BAP1. m6A-binding protein, YTHDF2 recognized and decayed methylated mRNA of BAP1, leading to the reduced BAP1 stability. The FTO/BAP1 axis promoted MPP-induced ferroptosis by suppressing SLC7A11. BAP1, in collaboration with p53, reduced the level of expression of SLC7A11. Knocking down BAP1 mitigated ferroptosis in an MPTP mouse model. : m6A-mediated modification of BAP1 regulates neuronal ferroptosis by cooperating with p53 to decrease the level of SLC7A11. Thus, BAP1 may be a potential therapeutic target for PD treatment.
帕金森病（PD）是一种神经退行性疾病，其病理机制涉及铁死亡。在本研究中，评估了乳腺癌1号相关蛋白1（BAP1）对PD中神经元铁死亡的影响及机制。
通过向小鼠注射MPTP构建PD小鼠模型。采用尼氏染色、免疫组织化学、免疫荧光和普鲁士蓝染色评估组织病理学和铁分布。通过使SK-N-SH细胞暴露于MPP构建PD细胞模型。通过MeRIP评估BAP1的m6A水平。利用RT-qPCR评估BAP1、FTO、IGF2BP1、METTL3、YTHDF2和SLC7A11的mRNA水平。通过蛋白质免疫印迹法检测BAP1、FTO、IGF2BP1、METTL3、YTHDF2、SLC7A11和p53的蛋白质水平。使用CCK-8法评估细胞活力，并使用TUNEL法评估细胞凋亡。还测量了丙二醛（MDA）、谷胱甘肽（GSH）、超氧化物歧化酶（SOD）和铁的水平。使用RNA免疫沉淀（RIP）法、双荧光素酶报告基因检测法和染色质免疫沉淀（ChIP）法验证分子间的相互作用。
用MPP处理的SK-N-SH细胞显示BAP1的整体m6A水平降低。FTO促进BAP1的m6A去甲基化，导致BAP1表达水平升高。m6A结合蛋白YTHDF2识别并降解BAP1的甲基化mRNA，导致BAP1稳定性降低。FTO/BAP1轴通过抑制SLC7A11促进MPP诱导的铁死亡。BAP1与p53协同作用，降低SLC7A11的表达水平。敲低BAP1可减轻MPTP小鼠模型中的铁死亡。
m6A介导的BAP1修饰通过与p53协同作用降低SLC7A11水平来调节神经元铁死亡。因此，BAP1可能是PD治疗的潜在靶点。
