title: A centronuclear myopathy--dynamin 2 mutation impairs autophagy in mice.
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.
authors.affiliation: UM76, Université Pierre et Marie Curie-Paris 6, Paris, F-75013, France.
authors.forename: Anne-Cécile
authors.initials: AC
authors.lastname: Durieux
authors.forename: Stéphane
authors.initials: S
authors.lastname: Vassilopoulos
authors.forename: Jeanne
authors.initials: J
authors.lastname: Lainé
authors.forename: Bodvaël
authors.initials: B
authors.lastname: Fraysse
authors.forename: Laura
authors.initials: L
authors.lastname: Briñas
authors.forename: Bernard
authors.initials: B
authors.lastname: Prudhon
authors.forename: Josiane
authors.initials: J
authors.lastname: Castells
authors.forename: Damien
authors.initials: D
authors.lastname: Freyssenet
authors.forename: Gisèle
authors.initials: G
authors.lastname: Bonne
authors.forename: Pascale
authors.initials: P
authors.lastname: Guicheney
authors.forename: Marc
authors.initials: M
authors.lastname: Bitoun
mesh_terms: D000818:Animals; D001343:Autophagy; D004195:Disease Models, Animal; D034285:Dynamin II / Q000235:genetics* / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism; D005786:Gene Expression Regulation; D005838:Genotype; D006003:Glycogen / Q000378:metabolism; D006720:Homozygote; D008099:Liver / Q000378:metabolism; D008247:Lysosomes / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D020914:Myopathies, Structural, Congenital / Q000235:genetics* / Q000378:metabolism*; D013347:Subcellular Fractions; D013997:Time Factors
chemical_list: D006003:Glycogen; D034285:Dynamin II