A high-fidelity microfluidic platform reveals retrograde propagation as the main mechanism of α-Synuclein spread in human neurons

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Vroman, Rozan and de Lichtervelde, Lorenzo and Singh Dolt, Karamjit and Robertson, Graham and Kriek, Marco and Barbato, Michela and Cholewa-Waclaw, Justyna and Kunath, Tilo and Downey, Patrick and Zagnoni, Michele (2025) A high-fidelity microfluidic platform reveals retrograde propagation as the main mechanism of α-Synuclein spread in human neurons. npj Parkinson's Disease. (In Press) (https://doi.org/10.1038/s41531-025-00936-x)

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Abstract

α-Synuclein (αSyn) is a major component of Lewy bodies and Lewy neurites, which are a pathological hallmark of Parkinson’s disease (PD). Pathologically aggregated forms of αSyn can spread along neurites and induce the misfolding of normal αSyn. To elucidate how αSyn pathology propagates between brain areas, we developed a novel in vitro microfluidic platform to study the intracellular transport of preformed fibrils and the induction and spread of αSyn aggregates. Patient-derived midbrain dopaminergic (mDA) neurons were cultured in microfluidic devices designed to maintain unidirectional axonal connections between fluidically isolated mDA neuronal cultures for over 3 months. Using αSyn preformed fibrils to induce Lewy-like pathology, we found that anterograde spread of αSyn fibrils was slow and occurred at low levels, while retrograde spread was significantly more efficient. This is in line with observations in animal models and shows that the platform provides an innovative new tool for studying PD in vitro.

ORCID iDs

Vroman, Rozan ORCID logoORCID: https://orcid.org/0000-0002-9347-3442, de Lichtervelde, Lorenzo, Singh Dolt, Karamjit, Robertson, Graham, Kriek, Marco, Barbato, Michela, Cholewa-Waclaw, Justyna, Kunath, Tilo, Downey, Patrick and Zagnoni, Michele ORCID logoORCID: https://orcid.org/0000-0003-3198-9491;
CORE (COnnecting REpositories)