IPSC-DERIVED EXTRACELLULAR VESICLES RESCUE PARKINSON’S DISEASE–ASSOCIATED DEFICITS IN HUMAN AND MOUSE MODELS

Parkinson's disease (PD) pathogenesis often involves progressive α-synuclein (α-Syn)-mediated neuronal dysfunction, yet the earliest cellular events that link α-Syn pathology to circuit failure remain poorly defined. Here, we used human-induced pluripotent stem cell (iPSC)-derived dopaminergic (DA) neurons from patients carrying the familial A53T SNCA mutation to reconstruct the temporal course of dysfunction in vitro. We identified a biphasic trajectory: an early phase of hyperexcitability characterized by less depolarized action potential firing thresholds and elevated spontaneous firing, followed by a progressive shift toward hypoexcitability as the neurons mature, accompanied by reduced network activity, synaptic failure, and α-Syn accumulation. Transcriptomic profiling at the critical transition point revealed a dual transcriptional signature, characterized by the upregulation of stress-inflammatory pathways (p53, JAK-STAT, apoptosis) and the systematic downregulation of metabolic and synaptic maintenance genes. This molecular profile preceded functional collapse, linking early hyperactivity-driven metabolic stress to subsequent neuronal exhaustion. To counteract this pathology, we used extracellular vesicles (EVs), small membrane-bound particles carrying intercellular signals, as a cell-free treatment approach. Strikingly, treatment with EVs derived from healthy iPSCs completely rescued both electrophysiological deficits and pathological α-Syn accumulation, restoring normal firing patterns, synaptic function, and network activity. Consistent with these observations, EV treatment reduced α-Syn aggregation and improved motor responses in α-Syn fibril–injected mice, which are characterized by pathological α-Syn accumulation and motor deficits. Overall, these findings demonstrate that EVs derived from healthy iPSCs can reverse PD-related phenotypes in human and mouse models.