A Centronuclear Myopathy - Dynamin 2 Mutation Impairs Autophagy in Mice

Anne-Cécile Durieux (1) , Stéphane Vassilopoulos (2) , Jeanne Lainé (3) , Bodvael Fraysse (4) , Laura Briñas , Bernard Prudhon (2) , Josiane Castells (1) , Damien Freyssenet (1) , Gisele Bonne (2) , Pascale Guicheney (5) , Marc Bitoun (2)

1 LIBM - Laboratoire Interuniversitaire de Biologie de la Motricité
2 Centre de recherche en Myologie – U974 SU-INSERM
3 NDC - Neurobiologie et diversité cellulaire
4 UMR 1089, Atlantic Gene Therapies
5 Coeur, Muscle et Vaisseaux

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.

Mots clés: Dynamin 2; Autophagosome maturation; Knock-In mouse model

Domaines: Sciences du Vivant [q-bio]

Anne-Cécile Durieux, Stéphane Vassilopoulos, Jeanne Lainé, Bodvael Fraysse, Laura Briñas, et al.. A Centronuclear Myopathy - Dynamin 2 Mutation Impairs Autophagy in Mice. Traffic, 2012, 13 (6), pp.869-879. ⟨10.1111/j.1600-0854.2012.01348.x⟩. ⟨hal-02453822⟩