Title :

Accumulation of free oligosaccharides and tissue damage in cytosolic α-mannosidase (Man2c1)-deficient mice

Author(s) :

Paciotti, Silvia [Auteur]
Persichetti, Emanuele [Auteur]
Klein, Katharina [Auteur]
Tasegian, Anna [Auteur]
Duvet, Sandrine [Auteur]
Hartmann, Dieter [Auteur]
Gieselmann, Volkmar [Auteur]
Beccari, Tommaso [Auteur]

Journal title :

The Journal of biological chemistry

Abbreviated title :

J. Biol. Chem.

Volume number :

289

Pages :

9611-9622

Publication date :

2014-04-04

ISSN :

1083-351X

English keyword(s) :

Intestine, Small
Glycogen
Oligosaccharide
Carbohydrate Metabolism
Bowman Capsule
Cytosolic α-Mannosidase
Telencephalon
Mannose
Gene Knockout
Cytosol
Mice, Knockout
Enterocytes
Animals
Kidney Tubules, Proximal
Fibrosis
Glycosidase
Mice
alpha-Mannosidase
Animal Models
Apoptosis
ER-associated Degradation

HAL domain(s) :

Chimie/Chimie théorique et/ou physique

English abstract : [en]

Free Man(7-9)GlcNAc2 is released during the biosynthesis pathway of N-linked glycans or from misfolded glycoproteins during the endoplasmic reticulum-associated degradation process and are reduced to Man5GlcNAc in the ...
Show more >Free Man(7-9)GlcNAc2 is released during the biosynthesis pathway of N-linked glycans or from misfolded glycoproteins during the endoplasmic reticulum-associated degradation process and are reduced to Man5GlcNAc in the cytosol. In this form, free oligosaccharides can be transferred into the lysosomes to be degraded completely. α-Mannosidase (MAN2C1) is the enzyme responsible for the partial demannosylation occurring in the cytosol. It has been demonstrated that the inhibition of MAN2C1 expression induces accumulation of Man(8-9)GlcNAc oligosaccharides and apoptosis in vitro. We investigated the consequences caused by the lack of cytosolic α-mannosidase activity in vivo by the generation of Man2c1-deficient mice. Increased amounts of Man(8-9)GlcNAc oligosaccharides were recognized in all analyzed KO tissues. Histological analysis of the CNS revealed neuronal and glial degeneration with formation of multiple vacuoles in deep neocortical layers and major telencephalic white matter tracts. Enterocytes of the small intestine accumulate mannose-containing saccharides and glycogen particles in their apical cytoplasm as well as large clear vacuoles in retronuclear position. Liver tissue is characterized by groups of hepatocytes with increased content of mannosyl compounds and glycogen, some of them undergoing degeneration by hydropic swelling. In addition, lectin screening showed the presence of mannose-containing saccharides in the epithelium of proximal kidney tubules, whereas scattered glomeruli appeared collapsed or featured signs of fibrosis along Bowman's capsule. Except for a moderate enrichment of mannosyl compounds and glycogen, heterozygous mice were normal, arguing against possible toxic effects of truncated Man2c1. These findings confirm the key role played by Man2c1 in the catabolism of free oligosaccharides.Show less >

Language :

Anglais

Administrative institution(s) :

CNRS
Université de Lille

Collections :

• Unité de Glycobiologie Structurale et Fonctionnelle (UGSF) - UMR 8576

Research team(s) :

Mécanismes moléculaires de la N-glycosylation et pathologies associées

Submission date :

2020-02-12T15:12:04Z