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Article Dans Une Revue Cell Reports Année : 2018

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

Céline Lustremant
  • Fonction : Auteur
Marion Poirel
  • Fonction : Auteur
Kostantin Dobrenis
  • Fonction : Auteur
Jean-Philippe Puech
  • Fonction : Auteur
Alexandra Durr
Alexis Brice
  • Fonction : Auteur
Giovanni Stevanin

Résumé

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.
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Dates et versions

hal-02347820 , version 1 (05-11-2019)

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Paternité - Pas d'utilisation commerciale - Pas de modification

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Maxime Boutry, Julien Branchu, Céline Lustremant, Claire Pujol, Julie Pernelle, et al.. Inhibition of Lysosome Membrane Recycling Causes Accumulation of Gangliosides that Contribute to Neurodegeneration. Cell Reports, 2018, 23 (13), pp.3813-3826. ⟨10.1016/j.celrep.2018.05.098⟩. ⟨hal-02347820⟩
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