Retinoic acid alleviates manganese-induced neurotoxicity in SH-SY5Y cells via the Trim28/α-synuclein/H4K91ac epigenetic axis.

BACKGROUND: Manganese (Mn)-induced neurotoxicity is a major public health concern. The aim of this study is to assess whether retinoic acid, a metabolite of vitamin A, can counteract manganese-induced neurotoxicity in SH-SY5Y cells by counteracting epigenetic dysregulation. METHODS: In vivo, we assessed neurobehavioral function, striatal pathology, synaptic ultrastructure, Mn content, dopamine levels, and expression of Trim28, α-synuclein (α-syn), H4K91ac, and DAT in Mn exposed rats. In vitro, we investigated the interactions between α-syn, Trim28 and H4 using immunofluorescence, molecular docking and immunoprecipitation techniques. We used chromatin immunoprecipitation to detect the enrichment of H4K91ac within the DAT promoter region. Additionally, we knocked down α-syn and Trim28 using siRNA to explore their potential molecular mechanisms. RESULTS: Mn exposure induced behavioral deficits, synaptic damage, and dopaminergic dysfunction in rats. Mechanistically, Trim28 mediated α-syn nuclear translocation. Nuclear α-syn bound histone H4, reducing H4K91ac enrichment at the DAT promoter, suppressing DAT expression, and disrupting dopamine homeostasis. Knockdown of Trim28 or α-syn reversed these effects. Retinoic acid inhibits the nuclear translocation of α-syn by modulating Trim28, and restores the levels of H4K91ac and DAT, thereby alleviating manganese-induced neurotoxicity in cells. CONCLUSION: This study elucidates the role of the Trim28/α-syn/H4K91ac axis in manganese-induced dopaminergic dysfunction and identifies Trim28 as a potential target for retinoic acid.