title: Tunneling nanotubes spread fibrillar α-synuclein by intercellular trafficking of lysosomes.
abstract: Synucleinopathies such as Parkinson's disease are characterized by the pathological deposition of misfolded α-synuclein aggregates into inclusions throughout the central and peripheral nervous system. Mounting evidence suggests that intercellular propagation of α-synuclein aggregates may contribute to the neuropathology; however, the mechanism by which spread occurs is not fully understood. By using quantitative fluorescence microscopy with co-cultured neurons, here we show that α-synuclein fibrils efficiently transfer from donor to acceptor cells through tunneling nanotubes (TNTs) inside lysosomal vesicles. Following transfer through TNTs, α-synuclein fibrils are able to seed soluble α-synuclein aggregation in the cytosol of acceptor cells. We propose that donor cells overloaded with α-synuclein aggregates in lysosomes dispose of this material by hijacking TNT-mediated intercellular trafficking. Our findings thus reveal a possible novel role of TNTs and lysosomes in the progression of synucleinopathies.
authors.affiliation: Institut Pasteur, Unité Trafic Membranaire et Pathogénèse, Paris Cedex 15, France.
authors.forename: Saïda
authors.initials: S
authors.lastname: Abounit
authors.affiliation: Paris-Saclay Institute of Neuroscience, CNRS, Gif-sur-Yvette, France.
authors.forename: Luc
authors.initials: L
authors.lastname: Bousset
authors.affiliation: Institut Pasteur, Unité Trafic Membranaire et Pathogénèse, Paris Cedex 15, France.
authors.forename: Frida
authors.initials: F
authors.lastname: Loria
authors.affiliation: Institut Pasteur, Unité Trafic Membranaire et Pathogénèse, Paris Cedex 15, France.
authors.forename: Seng
authors.initials: S
authors.lastname: Zhu
authors.affiliation: Laboratoire d'Analyse d'Images Quantitative, Institut Pasteur, Paris Cedex 15, France.
authors.forename: Fabrice
authors.initials: F
authors.lastname: de Chaumont
authors.affiliation: Paris-Saclay Institute of Neuroscience, CNRS, Gif-sur-Yvette, France.
authors.forename: Laura
authors.initials: L
authors.lastname: Pieri
authors.affiliation: Laboratoire d'Analyse d'Images Quantitative, Institut Pasteur, Paris Cedex 15, France.
authors.forename: Jean-Christophe
authors.initials: JC
authors.lastname: Olivo-Marin
authors.affiliation: Paris-Saclay Institute of Neuroscience, CNRS, Gif-sur-Yvette, France.
authors.forename: Ronald
authors.initials: R
authors.lastname: Melki
authors.affiliation: Institut Pasteur, Unité Trafic Membranaire et Pathogénèse, Paris Cedex 15, France chiara.zurzolo@pasteur.fr.
authors.forename: Chiara
authors.initials: C
authors.lastname: Zurzolo
mesh_terms: D000682:Amyloid / Q000378:metabolism*; D000818:Animals; D002450:Cell Communication; D002478:Cells, Cultured; D018920:Coculture Techniques; D008247:Lysosomes / Q000378:metabolism*; D051379:Mice; D008856:Microscopy, Fluorescence; D043942:Nanotubes; D009474:Neurons / Q000502:physiology*; D051844:alpha-Synuclein / Q000378:metabolism*
chemical_list: D000682:Amyloid; D051844:alpha-Synuclein
keywords: TNTs; intercellular transfer; synucleinopathies; α‐synuclein