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A Centronuclear Myopathy - Dynamin 2 Mutation Impairs Autophagy in Mice
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International audience. Dynamin 2 (Dnm2) is involved in endocytosis and intracellular membrane trafficking through its function in vesicle formation from distinct membrane compartments. Heterozygous mutations in the DNM2 gene cause dominant centronuclear myopathy or Charcot-Marie-Tooth neuropathy. We generated a knock-in KI-Dnm2 R465W mouse model expressing the most frequent human mutation and recently reported that heterozygous mice progressively developed a myopathy. We investigated here the cause of neonatal lethality occurring in homozygous mice. We show that homozygous 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 homozygous embryonic fibroblasts point out to a decrease in the autophagy flux prior to degradation at the autolysosome. We show that starved homozygous cells have a higher number of autophagy-related structures which remain in immature stages probably due to a defect of acidification. Our results highlight the role of Dnm2 in the crosstalk 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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