A centronuclear myopathy--dynamin 2 mutation impairs autophagy in mice |
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Authors: | Durieux Anne-Cécile Vassilopoulos Stéphane Lainé Jeanne Fraysse Bodvaël Briñas Laura Prudhon Bernard Castells Josiane Freyssenet Damien Bonne Gisèle Guicheney Pascale Bitoun Marc |
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Institution: | UM76, Université Pierre et Marie Curie-Paris 6, Paris, F-75013, France. |
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Abstract: | Dynamin 2 (Dnm2) is involved in endocytosis and intracellular membrane trafficking through its function in vesicle formation from distinct membrane compartments. Heterozygous (HTZ) mutations in the DNM2 gene cause dominant centronuclear myopathy or Charcot-Marie-Tooth neuropathy. We generated a knock-in Dnm2R465W mouse model expressing the most frequent human mutation and recently reported that HTZ mice progressively developed a myopathy. We investigated here the cause of neonatal lethality occurring in homozygous (HMZ) mice. We show that HMZ mice present at birth with a reduced body weight, hypoglycemia, increased liver glycogen content and hepatomegaly, in agreement with a defect in neonatal autophagy. In vitro studies performed in HMZ embryonic fibroblasts point out to a decrease in the autophagy flux prior to degradation at the autolysosome. We show that starved HMZ cells have a higher number of immature autophagy-related structures probably due to a defect of acidification. Our results highlight the role of Dnm2 in the cross talk between endosomal and autophagic pathways and evidence a new role of Dnm2-dependent membrane trafficking in autophagy which may be relevant in DNM2-related human diseases. |
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Keywords: | autophagosome maturation dynamin 2 knock‐in mouse model neonatal autophagy |
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