Microglial activation and alpha-synuclein oligomers drive the early inflammatory phase of Parkinson's disease

Evans, J. R.; Grant-Peters, M.; Beckwith, J. S.; Toomey, C. E.; Popovic, R.; Breiter, J. C.; Brenton, J. W.; Fairbrother-Browne, A.; Strohbuecker, S.; Lachica, J.; Rodriguez-Lopez, M.; Brock, E. E.; Fu, B.; Nahidiazar, L.; Lopez-Garcia, P.; Ferguson, R.; Saleeb, R. S.; Lucas-Clarke, H.; Penverne, A.; D'Sa, K.; Pang, C. W.; Horrocks, M. H.; Vendruscolo, M.; Wood, N.; Lee, S. F.; Ryten, M.; Gandhi, S.

doi:10.1101/2025.08.25.671921

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bioRxiv · 10.1101/2025.08.25.671921

Microglial activation and alpha-synuclein oligomers drive the early inflammatory phase of Parkinson's disease

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Abstract

Parkinsons disease (PD) is characterised by insoluble -synuclein (Syn) 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 Syn within cortical microglia. In hiPSC-derived microglia, both endogenous Syn 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 Syn oligomerisation potently initiates early neuroinflammation, highlighting a critical interplay between proteinopathy and immune activation at the earliest stages of disease.

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Evans, J. R., Grant-Peters, M., Beckwith, J. S., Toomey, C. E., Popovic, R., Breiter, J. C., Brenton, J. W., Fairbrother-Browne, A., Strohbuecker, S., Lachica, J., Rodriguez-Lopez, M., Brock, E. E., Fu, B., Nahidiazar, L., Lopez-Garcia, P., Ferguson, R., Saleeb, R. S., Lucas-Clarke, H., Penverne, A., D'Sa, K., Pang, C. W., Horrocks, M. H., Vendruscolo, M., Wood, N., Lee, S. F., Ryten, M., Gandhi, S.. 2025-08-28. Microglial activation and alpha-synuclein oligomers drive the early inflammatory phase of Parkinson's disease. https://doi.org/10.1101/2025.08.25.671921

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