H3K4ME1 AND H3K4ME3 EPIGENETIC MODULATION OF MICROGLIA IN PARKINSON’S DISEASE: IMPLICATIONS FOR DOPAMINERGIC NEURODEGENERATION

Parkinson’s disease (PD) is characterized by the progressive loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc), with microglia playing a central role in sustaining chronic neuroinflammation. The mechanisms underlying persistent microglial activation in PD remain poorly defined. To delineate microglial responses under prolonged inflammatory conditions, we exposed primary microglia to repetitive stimulation with LPS and IFN-g in vitro. Compared to the activation elicited by a single challenge, repeated exposure attenuated nitrite production, reduced microglia reactivity and impaired exacerbated phagocytosis of dopaminergic neurons. Nuclear translocation of NF-kB was also diminished, indicative of a tolerant or anergic phenotype. Epigenetic profiling revealed increased enrichment of H3K4me1 and H3K4me3 marks following repetitive stimulation, suggesting transcriptional reprogramming associated with a tolerant phenotype. To assess clinical relevance, we examined microglial epigenetic signatures in postmortem PD tissue. Significant differences were observed between PD and control samples, including an increase of CD16 expression, and the presence of ball-and-chain microglia, consistent with an exacerbated phagocytic phenotype rather than tolerance. These findings imply that tolerance mechanisms may be disrupted in PD, favoring sustained reactivity. Moreover, we are currently investigating epigenetic alterations of H3K4me1 and H3K4me3 in PD models in rats and mice to better elucidate the role of microglial cells in this neuroinflammatory context. Elucidating the interplay between NF-kB oscillatory dynamics and epigenetic modifications may clarify the molecular basis of microglial phenotypic programming. Understanding impaired tolerance in parkinsonian microglia could help finding therapeutic strategies aimed at mitigating neuroinflammation and slowing disease progression.