title: Hyposialylation of neprilysin possibly affects its expression and enzymatic activity in hereditary inclusion-body myopathy muscle.
abstract: Autosomal recessive hereditary inclusion-body myopathy (h-IBM) is caused by mutations of the UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase gene, a rate-limiting enzyme in the sialic acid metabolic pathway. Previous studies have demonstrated an abnormal sialylation of glycoproteins in h-IBM. h-IBM muscle shows the abnormal accumulation of proteins including amyloid-beta (Abeta). Neprilysin (NEP), a metallopeptidase that cleaves Abeta, is characterized by the presence of several N-glycosylation sites, and changes in these sugar moieties affect its stability and enzymatic activity. In the present study, we found that NEP is hyposialylated and its expression and enzymatic activity reduced in all h-IBM muscles analyzed. In vitro, the experimental removal of sialic acid by Vibrio Cholerae neuraminidase in cultured myotubes resulted in reduced expression of NEP. This was most likely because of a post-translational modification consisting in an abnormal sialylation of the protein that leads to its reduced stability. Moreover, treatment with Vibrio Cholerae neuraminidase was associated with an increased immunoreactivity for Abeta mainly in the form of distinct cytoplasmic foci within myotubes. We hypothesize that, in h-IBM muscle, hyposialylated NEP has a role in hampering the cellular Abeta clearing system, thus contributing to its abnormal accumulation within vulnerable fibers and possibly promoting muscle degeneration.
authors.affiliation: Department of Neuroscience, Catholic University, School of Medicine, Rome, Italy. a.broccolini@rm.unicatt.it
authors.forename: Aldobrando
authors.initials: A
authors.lastname: Broccolini
authors.forename: Teresa
authors.initials: T
authors.lastname: Gidaro
authors.forename: Raimondo
authors.initials: R
authors.lastname: De Cristofaro
authors.forename: Roberta
authors.initials: R
authors.lastname: Morosetti
authors.forename: Carla
authors.initials: C
authors.lastname: Gliubizzi
authors.forename: Enzo
authors.initials: E
authors.lastname: Ricci
authors.forename: Pietro A
authors.initials: PA
authors.lastname: Tonali
authors.forename: Massimiliano
authors.initials: M
authors.lastname: Mirabella
mesh_terms: D000328:Adult; D016229:Amyloid beta-Peptides / Q000096:biosynthesis*; D002478:Cells, Cultured; D025063:Chromosome Disorders / Q000201:enzymology / Q000235:genetics / Q000503:physiopathology; D015536:Down-Regulation / Q000187:drug effects / Q000502:physiology; D005260:Female; D005808:Genes, Recessive / Q000235:genetics; D006031:Glycosylation; D006801:Humans; D008297:Male; D018485:Muscle Fibers, Skeletal / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D018482:Muscle, Skeletal / Q000201:enzymology* / Q000503:physiopathology; D018979:Myositis, Inclusion Body / Q000201:enzymology* / Q000235:genetics / Q000503:physiopathology; D019158:N-Acetylneuraminic Acid / Q000378:metabolism*; D015260:Neprilysin / Q000378:metabolism*; D009439:Neuraminidase / Q000737:chemistry
chemical_list: D016229:Amyloid beta-Peptides; D009439:Neuraminidase; D015260:Neprilysin; D019158:N-Acetylneuraminic Acid