Objective: To explore the impact of α-synuclein (αS) on PRMT5.

Background: Alpha-synuclein (αS) is recognized as the pivotal molecule in the pathomechanism of Parkinson’s disease. Previous investigations have delineated that the overexpression of αS elicits both cytotoxic and cytoprotective epigenomic modifications, encompassing histone alterations. Nevertheless, the precise molecular mechanism and pathological significance remain elusive. Recently, we discerned an interaction between αS and the PRMT5-BAF (protein arginine methyltransferase 5 – BRG1/BRM-associated factor) complex, renowned for its role in coordinating the regulation of various genes through specific histone methylation.

Method: Neuronal-differentiated SH-SY5Y cells were procured via the administration of retinoic acid and brain-derived neurotrophic factor. Following αS induction, an analysis of histone modifications catalyzed by PRMT5 was conducted utilizing SDS-PAGE. ChIP-seq and RNA-seq were performed subsequent to αS induction with or without PRMT5 inhibitor (EPZ015866). The sequencing reads were aligned to the human reference genome (CRCh38) and subjected to in-silico analysis utilizing MACS2, Deeptools, edgeR, Clusterprofiler, and IPA.

Results: SDS-PAGE confirmed an elevation in symmetrical dimethylation on H4R3 (H4R3me2s), one of the products catalyzed by PRMT5, under αS induction. ChIP-seq revealed the selective occupancy of several genes by αS-induced H4R3me2s. RNA-seq unveiled multiple differentially affected genes under αS induction and PRMT5 inhibition. Subsequent in-silico analysis and cell viability assay demonstrated that αS could impact the PRMT5-mediated cytoprotective pathway.

Conclusion: We observed that the PRMT5-mediated pathway was influenced by αS overexpression in neuronal cell. αS-induced epigenetic and transcriptional alterations are intricately associated with neuronal cell function and viability.

References: Takaaki Nakamura, Naoto Sugeno, Takafumi Hasegawa, et al. Alpha-synuclein promotes PRMT5-mediated H4R3me2s histone methylation by interacting with the BAF complex. FEBS J. 2023 Dec 17. doi: 10.1111/febs.17037.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/alpha-synuclein-affects-prmt5-mediated-cytoprotective-pathway-in-neuronally-differentiated-sh-sy5y-cell/