PODXL regulates the neuronal entry of α-synuclein aggregates

Neupane, S.; Sustic, L.; Maraio, L.; Bouris, V.; Mariutti, G.; Ribeiro, R.; Yin, J.-A.; Melki, R.; Legname, G.; De Cecco, E.; Aguzzi, A.

doi:10.64898/2026.10.15.759470

bioRxiv · 10.64898/2026.10.15.759470

PODXL regulates the neuronal entry of α-synuclein aggregates

Neupane, S.·Sustic, L.·Maraio, L.·Bouris, V.·Mariutti, G.·Ribeiro, R.·Yin, J.-A.·Melki, R.·Legname, G.·De Cecco, E.·Aguzzi, A.

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Abstract

Cell-to-cell transmission of -synuclein (-Syn) aggregates is a key event in Parkinson's disease (PD) pathogenesis, yet the neuronal surface factors that govern uptake of pathogenic -Syn fibrils remain undefined. We developed a flow cytometry-based CRISPR activation screen for modifiers of -Syn preformed fibril (PFF) uptake by human iPSC-derived cortical neurons. By interrogating 68 genes encoding cell-surface proteins prioritised by PD genetic associations, we identified podocalyxin-like protein 1 (PODXL) as a strong suppressor of -Syn fibril uptake. High-content imaging and PODXL cDNA overexpression confirmed reduced PFF uptake. Stable PODXL overexpression also reduced PFF-seeded pSynSer129 accumulation and uptake of structurally distinct recombinant and disease-derived -Syn fibrils. Conversely, shRNA-mediated PODXL knockdown increased -Syn PFF uptake, and analysis of PODXL domain-deletion and N-glycosylation mutants suggested that the ectodomain and N-glycosylation contribute to the PODXL-mediated reduction in uptake. Transcriptomic profiling further identified membrane metalloendopeptidase (MME) as a PODXL-responsive candidate mediator. MME activation and treatment with conditioned medium from MME-activated neurons reduced PFF uptake. Thiorphan, an MME inhibitor, partially attenuated the PODXL-associated reduction in uptake. Together, our findings identify PODXL as a neuronal brake on -Syn uptake and implicate its glycan-dependent surface properties together with MME-associated extracellular activity.

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Neupane, S., Sustic, L., Maraio, L., Bouris, V., Mariutti, G., Ribeiro, R., Yin, J.-A., Melki, R., Legname, G., De Cecco, E., Aguzzi, A.. 2026-10-21. PODXL regulates the neuronal entry of α-synuclein aggregates. https://doi.org/10.64898/2026.10.15.759470

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