SNCA triplication shapes neuronal extracellular vesicle biology and promotes microglial activation in patient-derived iPSC-based models of Parkinson's disease

Boumpoureka, I.; Heider, J.; Delcambre, S.; Kleine Borgmann, F. B.; Poret, A.; Boussaad, I.; Wilbertz, J. H.; Sommer, P.; Mittelbronn, M.; Gruenewald, A.; Gorgogietas, V.; Krueger, R.

doi:10.64898/2026.09.09.750343

bioRxiv · 10.64898/2026.09.09.750343

SNCA triplication shapes neuronal extracellular vesicle biology and promotes microglial activation in patient-derived iPSC-based models of Parkinson's disease

Boumpoureka, I.·Heider, J.·Delcambre, S.·Kleine Borgmann, F. B.·Poret, A.·Boussaad, I.·Wilbertz, J. H.·Sommer, P.·Mittelbronn, M.·Gruenewald, A.·Gorgogietas, V.·Krueger, R.

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Abstract

Extracellular vesicles (EVs) are emerging as key mediators of intercellular communication and potential biomarkers in Parkinson's disease (PD), yet how disease-causing genetic alterations shape neuronal EV biology remains incompletely understood. Here, we used PD-patient iPSC-derived midbrain dopaminergic neurons (mDANs) harboring SNCA triplication (SNCA-4x), gene-corrected controls (SNCA-GC), and SNCA knockout (SNCA-KO) to investigate the impact of -synuclein overexpression on neuronal-enriched EV (nEV) biology and neuron to microglia communication. SNCA-4x mDANs exhibited marked transcriptional alterations in pathways related to vesicle trafficking and extracellular matrix organization. Using an optimized isolation workflow, SNCA-4x neurons released significantly more and smaller nEVs enriched in -synuclein, mitochondrial DNA (mtDNA), and PARK7/DJ-1 mRNA, while displaying reduced acetylcholinesterase activity. Functionally, SNCA-4x-derived nEVs were taken up more efficiently by isogenic control iPSC-derived microglia than SNCA-GC nEVs and induced stronger pro-inflammatory activation than both SNCA-GC nEVs and untreated microglia, characterized by altered microglial morphology and increased TNF- and IL-1{beta}, consistent with damage-associated molecular pattern (DAMP)-mediated signaling. Together, these findings demonstrate that SNCA-4x reshapes the properties and molecular cargo of nEVs, enhancing their capacity to trigger microglial activation, and identify EV-associated -synuclein, mtDNA, and PARK7 mRNA as candidate mechanistic and biomarker features in PD.

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Boumpoureka, I., Heider, J., Delcambre, S., Kleine Borgmann, F. B., Poret, A., Boussaad, I., Wilbertz, J. H., Sommer, P., Mittelbronn, M., Gruenewald, A., Gorgogietas, V., Krueger, R.. 2026-09-15. SNCA triplication shapes neuronal extracellular vesicle biology and promotes microglial activation in patient-derived iPSC-based models of Parkinson's disease. https://doi.org/10.64898/2026.09.09.750343

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