title: Autophagosome maturation is impaired in Fabry disease.
abstract: Fabry disease is a lysosomal storage disorder (LSD) caused by a deficiency in α-galactosidase A. The disease is characterized by severe major organ involvement, but the pathologic mechanisms responsible have not been elucidated. Disruptions of autophagic processes have been reported for other LSDs, but have not yet been investigated in Fabry disease. Renal biopsies were obtained from 5 adult male Fabry disease patients before and after 3 years of enzyme replacement therapy (ERT) with agalsidase alfa. Vacuole accumulation was seen in renal biopsies from all patients compared with control biopsies. Decreases in the number of vacuoles were seen after 3 years of ERT primarily in renal endothelial cells and mesangial cells. Measurement of the levels of LC3, a specific autophagy marker, in cultured cells from Fabry patients revealed increased basal levels compared to cells from non-Fabry subjects and a larger increase in response to starvation than seen in non-Fabry cells. Starvation in the presence of protease inhibitors did not result in a significant increase in LC3 in Fabry cells, whereas a further increase in LC3 was observed in non-Fabry cells, an observation that is consistent with impaired autophagic flux in Fabry disease. Overexpression of LC3 mRNA in Fabry fibroblasts compared to control cells is consistent with an upregulation of autophagy. Furthermore, LC3 and p62/SQSTM1 (that binds to LC3) staining in renal tissues and in cultured fibroblasts from Fabry patients supports impairment of autophagic flux. These findings suggest that Fabry disease is linked to a deregulation of autophagy.
authors.affiliation: Laboratoire de Biochimie Médicale, Rouen University Hospital and EA 4309, University of Rouen, Rouen, France.
authors.forename: Marc
authors.initials: M
authors.lastname: Chévrier
authors.forename: Noureddine
authors.initials: N
authors.lastname: Brakch
authors.forename: Lesueur
authors.initials: L
authors.lastname: Céline
authors.forename: Damien
authors.initials: D
authors.lastname: Genty
authors.forename: Yasmina
authors.initials: Y
authors.lastname: Ramdani
authors.forename: Solange
authors.initials: S
authors.lastname: Moll
authors.forename: Mojgan
authors.initials: M
authors.lastname: Djavaheri-Mergny
authors.forename: Carole
authors.initials: C
authors.lastname: Brasse-Lagnel
authors.forename: Annie Laquerrière
authors.initials: AL
authors.lastname: Annie Laquerrière
authors.forename: Frédéric
authors.initials: F
authors.lastname: Barbey
authors.forename: Soumeya
authors.initials: S
authors.lastname: Bekri
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000328:Adult; D001343:Autophagy / Q000187:drug effects; D001706:Biopsy; D015153:Blotting, Western; D056947:Enzyme Replacement Therapy; D000795:Fabry Disease / Q000188:drug therapy / Q000473:pathology*; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D007527:Isoenzymes / Q000494:pharmacology / Q000627:therapeutic use; D007668:Kidney / Q000187:drug effects / Q000473:pathology / Q000648:ultrastructure; D008297:Male; D018613:Microscopy, Confocal; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism; D008875:Middle Aged; D010588:Phagosomes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology* / Q000648:ultrastructure; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins; D000071456:Sequestosome-1 Protein; D014617:Vacuoles / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D000519:alpha-Galactosidase / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D007527:Isoenzymes; C477012:MAP1LC3A protein, human; D008869:Microtubule-Associated Proteins; D012333:RNA, Messenger; D011994:Recombinant Proteins; C099718:SQSTM1 protein, human; D000071456:Sequestosome-1 Protein; C000627036:agalsidase alfa; D000519:alpha-Galactosidase