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.
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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