A potential therapeutic target for spastic paraplegia 11 / amyotrophic lateral sclerosis 5

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

By : Maxime Boutry, Julien Branchu, Celine Lustremant, Claire Pujol, Julie Pernelle,
Raphael 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,
and Frederic Darios

Cell Reports 2018, 23, 3813–3826

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  ccumulation 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.

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