Scientists from the Institut Pasteur have demonstrated the role of lysosomal vesicles in transporting α-synuclein aggregates, responsible for Parkinson's and other neurodegenerative diseases, between neurons. These proteins move from one neuron to the next in lysosomal vesicles which travel along the "tunneling nanotubes" between cells. These findings were published in The EMBO Journal on August 22, 2016.
Synucleinopathies, a group of neurodegenerative diseases including Parkinson’s disease, are characterized by the pathological deposition of aggregates of the misfolded α-synuclein protein into inclusions throughout the central and peripheral nervous system. Intercellular propagation (from one neuron to the next) of α-synuclein aggregates contributes to the progression of the neuropathology, but little was known about the mechanism by which spread occurs.
In this study, scientists from the Membrane Traffic and Pathogenesis Unit, directed by Chiara Zurzolo at the Institut Pasteur, used fluorescence microscopy to demonstrate that pathogenic α-synuclein fibrils travel between neurons in culture, inside lysosomal vesicles through tunneling nanotubes (TNTs), a new mechanism of intercellular communication.
Image : Neuronal cells connected by TNTs which containing synuclein fibrils (aggregates in red) inside. On the right: 3D visualization. © Institut Pasteur
After being transferred via TNTs, α-synuclein fibrils are able to recruit and induce aggregation of the soluble α-synuclein protein in the cytosol of cells receiving the fibrils, thus explaining the propagation of the disease. The scientists propose that cells overloaded with α-synuclein aggregates in lysosomes dispose of this material by hijacking TNT-mediated intercellular trafficking. However, this results in the disease being spread to naive neurons.
This study demonstrates that TNTs play a significant part in the intercellular transfer of α-synuclein fibrils and reveals the specific role of lysosomes in this process. This represents a major breakthrough in understanding the mechanisms underlying the progression of synucleinopathies.
These compelling findings, together with previous reports from the same team, point to the general role of TNTs in the propagation of prion-like proteins in neurodegenerative diseases and identify TNTs as a new therapeutic target to combat the progression of these incurable diseases.
Tunneling nanotubes spread fibrillar α-synuclein by intercellular trafficking of lysosomes, The EMBO Journal, 22 August 2016
Saïda Abounit(1), Luc Bousset(2*), Frida Loria(1*) Seng Zhu(1*), Fabrice de Chaumont(3), Laura Pieri(2), Jean-Christophe Olivo-Marin(3), Ronald Melki(2) and Chiara Zurzolo(1)
(1) Institut Pasteur, Unité Trafic Membranaire et Pathogénèse, 25-28 Rue du Docteur Roux, 75724 Paris CEDEX 15, France.
(2) Paris-Saclay Institute of Neuroscience, CNRS, 91190, Gif-sur-Yvette, France.
(3) Institut Pasteur, Laboratoire d’Analyse d’Images Quantitative, 25-28 Rue du Docteur Roux, 75724 Paris CEDEX 15, France.
* Equal contributions