Modulation of retroviral capsid assembly halts ARC-mediated TDP-43 intercellular spreading
Jimenez-Zuniga, A.; Sanchez-Molleda, A.; Martinez-Ascension, A.; Jimenez-Salvador, I.; Fuentetaja, M.; Garcia ibarlucea, M.; Ramis Cortes, R.; Rodriguez-Gomez, L.; Hernandez-Eguiazu, H.; Alcain Dominguez, M.; Zuniga-Elizari, J. L.; Moragon Rodriguez, S.; Saez-Mas, A.; Blazquez, L.; Lafarga, V.; Fernandez Capetillo, O.; Leonardo, A.; Bergara, A.; Lopez de Munain Arregui, A.; Gil-Bea, F.; Gerenu Lopetegi, G.
Show abstract
Intercellular propagation of pathological TDP-43 drives the progression of ALS and FTD, yet the mechanisms enabling transmission remain elusive. Here, we demonstrate that Activity-regulated cytoskeleton associated protein (ARC/Arg3.1) is pathologically subverted to act as a retroviral-like capsid vehicle for TDP-43 spreading. In a Drosophila model, we reveal that massive Arc1 upregulation drives glia-to-neuron TDP-43 seeding, while its genetic ablation halts pathological transfer, improves motor function, and extends survival. In parallel human cellular models, stress-induced ARC colocalizes with TDP-43 to orchestrate its intercellular transmission. Guided by ARCs capsid architecture, we reproposed Lenacapavir, an FDA-approved HIV-1 capsid modulator, as a stable binder of ARC/Arg3.1 capsid interfaces. Lenacapavir treatment effectively blocks TDP-43 propagation in vitro and rescues disease phenotypes in vivo. Our findings establish ARC as a conserved vehicle for pathological protein transmission and deliver an immediately translatable pharmacological strategy to arrest disease progression in ALS and FTD.
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