Lysosome recycling problems in SPG11 HSP

Posted - September 2018 in Research Highlights

More understanding of the pathway involved

 

Autophagy is the process by which old or worn out structures in the cells of the body are recycled… Like scavenging or gobbling up these structures so that they don’t accumulate like garbage.

 

In SPG11 HSP, this study shows that membrane recycling of organelles called lysosomes is inhibited, and this leads to the accumulation of toxic compounds called gangliosides that are known to cause neurodegeneration.

 

Specifically, this study demonstrates that the protein Spatacsin, which is impaired in SPG11 HSP acts downstream of a second protein Clathrin, and works with a third protein Dynamin for normal lysosome membrane recycling and clearance of potentially toxic gangliosides from the organelle.

 

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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 Rep. 2018 Jun 26;23(13):3813-3826. doi: 10.1016/j.celrep.2018.05.098. PMID: 29949766

 

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

Boutry M1, Branchu J2, Lustremant C2, Pujol C2, Pernelle J2, Matusiak R2, Seyer A3, Poirel M3, Chu-Van E4, Pierga A2, Dobrenis K5, Puech JP6, Caillaud C6, Durr A7, Brice A2, Colsch B4, Mochel F8, El Hachimi KH1, Stevanin G9, Darios F10.

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: [email protected]

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: [email protected]

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