α-Synuclein (αS) is a key molecule in the pathomechanism of Parkinson's disease. Most studies on αS to date have focused on its function in the neuronal cytosol, but its action in the nucleus has also been postulated. Indeed, several lines of evidence indicate that overexpressed αS leads to epigenomic alterations. To clarify the functional role of αS in the nucleus and its pathological significance, HEK293 cells constitutively expressing αS were used to screen for nuclear proteins that interact with αS by nanoscale liquid chromatography/tandem mass spectrometry. Interactome analysis of the 229 identified nuclear proteins revealed that αS interacts with the BRG1-associated factor (BAF) complex, a family of multi-subunit chromatin remodelers important for neurodevelopment, and protein arginine methyltransferase 5 (PRMT5). Subsequent transcriptomic analysis also suggested a functional link between αS and the BAF complex. Based on these results, we analyzed the effect of αS overexpression on the BAF complex in neuronally differentiated SH-SY5Y cells and found that induction of αS disturbed the BAF maturation process, leading to a global increase in symmetric demethylation of histone H4 on arginine 3 (H4R3me2s) via enhanced BAF–PRMT5 interaction. Chromatin immunoprecipitation sequencing confirmed accumulated H4R3me2s methylation near the transcription start site of the neuronal cell adhesion molecule (NRCAM) gene, which has roles during neuronal differentiation. Transcriptional analyses confirmed the negative regulation of NRCAM by αS and PRMT5, which was reconfirmed by multiple datasets in the Gene Expression Omnibus (GEO) database. Taken together, these findings suggest that the enhanced binding of αS to the BAF complex and PRMT5 may cooperatively affect the neuronal differentiation process.

中文翻译：

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α-突触核蛋白通过与 BAF 复合物相互作用促进 PRMT5 介导的 H4R3me2s 组蛋白甲基化

α-突触核蛋白（αS）是帕金森病病理机制中的关键分子。迄今为止，大多数关于 αS 的研究都集中在其在神经元胞质中的功能，但也假设了其在细胞核中的作用。事实上，多项证据表明 αS 过度表达会导致表观基因组改变。为了阐明αS在细胞核中的功能作用及其病理意义，使用组成型表达αS的HEK293细胞，通过纳米级液相色谱/串联质谱法筛选与αS相互作用的核蛋白。对 229 个已识别核蛋白的相互作用组分析表明，αS 与 BRG1 相关因子 (BAF) 复合体（对神经发育很重要的多亚基染色质重塑家族）和蛋白精氨酸甲基转移酶 5 (PRMT5) 相互作用。随后的转录组分析也表明 αS 和 BAF 复合物之间存在功能联系。基于这些结果，我们分析了神经元分化的 SH-SY5Y 细胞中 αS 过表达对 BAF 复合物的影响，发现 αS 的诱导扰乱了 BAF 成熟过程，导致精氨酸 3 上组蛋白 H4 的对称去甲基化全面增加。 H4R3me2s）通过增强的 BAF-PRMT5 相互作用。染色质免疫沉淀测序证实，神经元细胞粘附分子 ( NRCAM )基因的转录起始位点附近积累了 H4R3me2s 甲基化，该基因在神经元分化过程中发挥作用。转录分析证实了 αS 和 PRMT5 对NRCAM的负调控，基因表达综合 (GEO) 数据库中的多个数据集再次证实了这一点。综上所述，这些发现表明 αS 与 BAF 复合物和 PRMT5 的结合增强可能会协同影响神经元分化过程。