Pathological α-synuclein dysregulates epitranscriptomic writer METTL3 to drive neuroinflammation in microglia

Recent reports suggest dysregulation of the N6-methyladenosine (m6A) RNA modification may contribute to the pathology of neurodegenerative diseases. Herein, we show the m6A methyltransferase complex including METTL3-the catalytic component of the nuclear-localized complex-is robustly upregulated in human microglia and astrocytes exposed to αSyn_f and Mn. Subcellular localization studies reveal METTL3 was predominantly cytoplasmic following Mn insult but remained nuclear following αSyn_f stimulation in activated microglia. Functional analysis revealed METTL3 and downstream m6A readers, including YTHDF2 and IGF2BP1-3, may regulate the proinflammatory secretome of activated microglia. Notably, methyltransferase activity and m6A abundance were significantly increased following Mn and αSyn_f treatment. METTL3 in Mn and αSyn_fin vivo models of neuroinflammation, along with human postmortem tissues from Alzheimer's disease (AD), Parkinson's disease (PD), and dementia with Lewy bodies (DLB) patients, was significantly upregulated. This was further confirmed by single-cell RNA sequencing (scRNA-seq) analysis. Overall, we demonstrate the m6A writer METTL3 may function as a major regulator of chronic neuroinflammation in synucleinopathies.