Alpha-synuclein Promotes PRMT5-mediated H4R3me2s Histone Methylation by Interacting with the BAF Complex.

alpha-Synuclein (alpha S) is a key molecule in the pathomechanism of Parkinson's disease. Most studies on alpha S 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 alpha S leads to epigenomic alterations. To clarify the functional role of alpha S in the nucleus and its pathological significance, HEK293 cells constitutively expressing alpha S were used to screen for nuclear proteins that interact with alpha S by nanoscale liquid chromatography/tandem mass spectrometry. Interactome analysis of the 229 identified nuclear proteins revealed that alpha S 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 alpha S and the BAF complex. Based on these results, we analyzed the effect of alpha S overexpression on the BAF complex in neuronally differentiated SH-SY5Y cells and found that induction of alpha S 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 alpha S 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 alpha S to the BAF complex and PRMT5 may cooperatively affect the neuronal differentiation process.