iPSC-derived extracellular vesicles rescue deficits in human and mouse models of Parkinsons disease

Rike, W. A.; Tripathi, U.; Hussien, Y.; Choudhary, A.; Rajkovic, A.; Sharma, O.; Rosh, I.; Manole, A.; Gage, F. H.; Houlden, H.; Brodski, C.; Stern, S.

doi:10.64898/2026.05.19.726142

bioRxiv · 10.64898/2026.05.19.726142

iPSC-derived extracellular vesicles rescue deficits in human and mouse models of Parkinsons disease

Rike, W. A.·Tripathi, U.·Hussien, Y.·Choudhary, A.·Rajkovic, A.·Sharma, O.·Rosh, I.·Manole, A.·Gage, F. H.·Houlden, H.·Brodski, C.·Stern, S.

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Abstract

Parkinsons disease (PD) pathogenesis often involves progressive -synuclein (-Syn)-mediated neuronal dysfunction, yet the earliest cellular events that link -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 a temporal course of dysfunction in vitro. We identified a biphasic trajectory with an early phase of hyperexcitability, characterized by elevated spontaneous firing, followed by a progressive transition into hypoexcitability as the neurons mature, accompanied by reduced network activity, synaptic dysfunction, and -Syn accumulation. Transcriptomic profiling at the critical transition point revealed a dual transcriptional signature, with upregulation of stress-inflammatory pathways (p53, JAK-STAT, apoptosis) coupled with 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 -Syn accumulation, restoring normal firing patterns, synaptic function, and network activity. Consistent with these observations, EV treatment reduced -Syn aggregation and improved motor responses in -Syn fibril-injected mice, which are characterized by pathological -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.

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Rike, W. A., Tripathi, U., Hussien, Y., Choudhary, A., Rajkovic, A., Sharma, O., Rosh, I., Manole, A., Gage, F. H., Houlden, H., Brodski, C., Stern, S.. 2026-05-26. iPSC-derived extracellular vesicles rescue deficits in human and mouse models of Parkinsons disease. https://doi.org/10.64898/2026.05.19.726142

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