Inhibition of Lysosome Membrane Recycling Causes Accumulation of Gangliosides that Contribute to Neurodegeneration.

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
Cell Reports. 2018-06-01; 23(13): 3813-3826
DOI: 10.1016/j.celrep.2018.05.098

PubMed
Lire sur PubMed



1. Cell Rep. 2018 Jun 26;23(13):3813-3826. doi: 10.1016/j.celrep.2018.05.098.

Inhibition of Lysosome Membrane Recycling Causes Accumulation of Gangliosides
that Contribute to Neurodegeneration.

Boutry M(1), Branchu J(2), Lustremant C(2), Pujol C(2), Pernelle J(2), Matusiak
R(2), Seyer A(3), Poirel M(3), Chu-Van E(4), Pierga A(2), Dobrenis K(5), Puech
JP(6), Caillaud C(6), Durr A(7), Brice A(2), Colsch B(4), Mochel F(8), El Hachimi
KH(1), Stevanin G(9), Darios F(10).

Author information:
(1)Sorbonne Université, F-75013 Paris, France; Inserm, U1127, F-75013 Paris,
France; CNRS, UMR 7225, F-75013 Paris, France; Institut du Cerveau et de la
Moelle Epinière (ICM), F-75013 Paris, France; Ecole Pratique des Hautes Etudes,
PSL Research University, Laboratoire de Neurogénétique, F-75013 Paris, France.
(2)Sorbonne Université, F-75013 Paris, France; Inserm, U1127, F-75013 Paris,
France; CNRS, UMR 7225, F-75013 Paris, France; Institut du Cerveau et de la
Moelle Epinière (ICM), F-75013 Paris, France.
(3)Profilomic SA, F-92100 Boulogne-Billancourt, France.
(4)Service de Pharmacologie et d’Immunoanalyse (SPI), Laboratoire d’Etude du
Métabolisme des Médicaments, CEA, INRA, Université Paris Saclay, MetaboHUB,
F-91191 Gif-sur-Yvette, France.
(5)Dominick P. Purpura Department of Neuroscience, Albert Einstein College of
Medicine, Bronx, NY 10461, USA.
(6)Laboratoire de Biochimie Métabolomique et Protéomique, Hôpital Universitaire
Necker-Enfants Malades, AP-HP, F-75015 Paris, France.
(7)Sorbonne Université, F-75013 Paris, France; Inserm, U1127, F-75013 Paris,
France; CNRS, UMR 7225, F-75013 Paris, France; Institut du Cerveau et de la
Moelle Epinière (ICM), F-75013 Paris, France; National Reference Center for
Neurogenetic Diseases, Pitié-Salpêtrière University Hospital, APHP, F-75013
Paris, France.
(8)Sorbonne Université, F-75013 Paris, France; Inserm, U1127, F-75013 Paris,
France; CNRS, UMR 7225, F-75013 Paris, France; Institut du Cerveau et de la
Moelle Epinière (ICM), F-75013 Paris, France; National Reference Center for
Neurogenetic Diseases, Pitié-Salpêtrière University Hospital, APHP, F-75013
Paris, France; Bioclinic and Genetic Unit of Neurometabolic Diseases,
Pitié-Salpêtrière University Hospital, F-75013 Paris, France.
(9)Sorbonne Université, F-75013 Paris, France; Inserm, U1127, F-75013 Paris,
France; CNRS, UMR 7225, F-75013 Paris, France; Institut du Cerveau et de la
Moelle Epinière (ICM), F-75013 Paris, France; Ecole Pratique des Hautes Etudes,
PSL Research University, Laboratoire de Neurogénétique, F-75013 Paris, France;
National Reference Center for Neurogenetic Diseases, Pitié-Salpêtrière University
Hospital, APHP, F-75013 Paris, France. Electronic address:
.
(10)Sorbonne Université, F-75013 Paris, France; Inserm, U1127, F-75013 Paris,
France; CNRS, UMR 7225, F-75013 Paris, France; Institut du Cerveau et de la
Moelle Epinière (ICM), F-75013 Paris, France. Electronic address:
.

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.

Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.

DOI: 10.1016/j.celrep.2018.05.098
PMCID: PMC6045775
PMID: 29949766 [Indexed for MEDLINE]

Auteurs Bordeaux Neurocampus