Inhibition of Lysosome Membrane Recycling Causes Accumulation of Gangliosides that Contribute to Neurodegeneration
Year: 2018
Type: article
Abstract: Lysosome membrane recycling occurs at the end of the autophagic pathway and requires proteins that are mostly encoded by genes mutated in neurodegenerative diseases. However, its implication in neuronal death is still unclear. Here, we show that spatacsin, which is required for lysosome recycling and whose loss of function leads to hereditary spastic paraplegia 11 (SPG11), promotes clearance of gangliosides from lysosomes in mouse and human SPG11 models. We demonstrate that spatacsin acts downstream of clathrin and recruits dynamin to allow lysosome membrane recycling and clearance of gangliosides from lysosomes. Gangliosides contributed to the accumulation of autophagy markers in lysosomes and to neuronal death. In contrast, decreasing ganglioside synthesis prevented neurodegeneration and improved motor phenotype in a SPG11 zebrafish model. Our work reveals how inhibition of lysosome membrane recycling leads to the deleterious accumulation of gangliosides, linking lysosome recycling to neurodegeneration.
Source: Cell Reports
Authors: Maxime Boutry, Julien Branchu, Céline Lustremant, Claire Pujol, Julie Pernelle, Raphaël Matusiak, Alexandre Seyer, Marion Poirel, Emeline Chu-Van, Alexandre Pierga, Kostantin Dobrenis, Jean-Philippe Puech, Catherine Caillaud, Alexandra Durr, Alexis Brice, Benoit Colsch, Fanny Mochel, Khalid Hamid El Hachimi, Giovanni Stevanin, Frédéric Darios
Institutions: Centre National de la Recherche Scientifique, Inserm, École Pratique des Hautes Études, Université Paris Sciences et Lettres, Sorbonne Université, Institut du Cerveau, Commissariat à l'Énergie Atomique et aux Énergies Alternatives, Université Paris-Saclay, Institut National de Recherche pour l'Agriculture, l'Alimentation et l'Environnement, CEA Paris-Saclay, MetaboHUB, Albert Einstein College of Medicine, Hôpital Necker-Enfants Malades, Assistance Publique – Hôpitaux de Paris, Pitié-Salpêtrière Hospital
Language: English
Subfield: Cellular and Molecular Neuroscience
Field: Neuroscience
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $4,764
Awards: G4148329670, Identification of new causative genes in spinocerebellar degenerations by combination of whole genome scan, next-generation sequencing and biological validation in vitro and in vivo, Infrastructure de Recherche Translationnelle pour les Biothérapies en Neurosciences, G7232962922, Integrated European –omics research project for diagnosis and therapy in rare neuromuscular and neurodegenerative diseases, G8467556417, Développement d'une infrastructure française distribuée pour la métabolomique dédiée à l'innovation
OpenAlex ID: W2811282160