Impaired a-Synuclein aggregate clearance in neuronal cells drive their spread to microglia through tunneling nanotubes.
Por:
Chakraborty R, Palese F, Samella P, Testa V, Montero-Muñoz J, Syan S, Nonaka T, Hasegawa M, Consiglio A and Zurzolo C
Publicada:
12 mar 2026
Ahead of Print:
12 mar 2026
Resumen:
Tunneling nanotubes (TNTs) play a crucial role in intercellular communication, enabling transfer of molecular cargoes over long distances between connected cells. Previous studies have demonstrated efficient, directional transfer of a-Synuclein (a-Syn) aggregates from neurons to microglia, with endosomal trafficking and lysosomal processing identified as the primary events following a-Syn internalization. Using human neuronal and microglial cell lines, we show that microglia exhibit higher lysosomal turnover, particularly through lysophagy, whereas neuronal lysosomes display compromised degradative capacity and impaired autophagic flux upon a-Syn exposure, resulting in compromised aggregate clearance. Such a response to a-Syn aggregates is also conserved in human iPSC-derived neurons and microglia. Moreover, perturbing aggregate clearance via autophagy inhibition enhances TNT-mediated transfer of a-Syn from neuronal cells to microglia. Microglia co-cultured with a-Syn-containing neurons upregulate autophagy flux, enabling efficient degradation of the transferred aggregates. These results highlight dysfunctional autophagy in neurons as a key driver outsourcing a-Syn aggregates to microglia.
Filiaciones:
Chakraborty R:
Institut Pasteur, CNRS UMR 3691, Université Paris Cité, Paris, France
Université Paris-Saclay, Gif-sur-Yvette, France
Palese F:
Institut Pasteur, CNRS UMR 3691, Université Paris Cité, Paris, France
Samella P:
Institut Pasteur, CNRS UMR 3691, Université Paris Cité, Paris, France
Trinity College, University of Cambridge, Cambridge, UK
Testa V:
Department of Pathology and Experimental Therapeutics, Bellvitge University Hospital-IDIBELL, 08908 Hospitalet de Llobregat, Spain, Institute of Biomedicine of the University of Barcelona (IBUB), Carrer Baldiri Reixac 15-21, Barcelona, Spain
Montero-Muñoz J:
Department of Pathology and Experimental Therapeutics, Bellvitge University Hospital-IDIBELL, 08908 Hospitalet de Llobregat, Spain, Institute of Biomedicine of the University of Barcelona (IBUB), Carrer Baldiri Reixac 15-21, Barcelona, Spain
Syan S:
Institut Pasteur, CNRS UMR 3691, Université Paris Cité, Paris, France
Nonaka T:
Dementia Research Project, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan
Hasegawa M:
Dementia Research Project, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan
Consiglio A:
Department of Pathology and Experimental Therapeutics, Bellvitge University Hospital-IDIBELL, 08908 Hospitalet de Llobregat, Spain, Institute of Biomedicine of the University of Barcelona (IBUB), Carrer Baldiri Reixac 15-21, Barcelona, Spain
Zurzolo C:
Institut Pasteur, CNRS UMR 3691, Université Paris Cité, Paris, France
Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Naples, Italy
Open Access
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