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SUMMARY Parkinson’s disease (PD) is characterised by insoluble α-synuclein (αSyn) aggregates in Lewy bodies (LBs) within the substantia nigra, with cortical pathology appearing as the disease progresses. Late-stage LB deposition, cellular stress, and neuronal loss obscure disease-driving events, we therefore performed multi-regional transcriptomic and aggregate profiling in early-midstage PD brains (Braak 3–4), where cortical regions are pathologically unaffected. We report neuroimmune activation as an early PD feature, characterised by the expansion of a high- SNCA -expressing microglial state. This robust immune signature occurs prior to LB formation, but is associated with oligomeric αSyn within cortical microglia. In hiPSC-derived microglia, both endogenous αSyn oligomerisation, and exogenous oligomer uptake, trigger transcriptional reprogramming, characterised by interferon-driven inflammation, antigen presentation, and mitochondrial suppression, closely mirroring the early PD brain. These findings describe mechanisms by which αSyn oligomerisation potently initiates early neuroinflammation, highlighting a critical interplay between proteinopathy and immune activation at the earliest stages of disease.
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