title: Role of LIMP-2 in the intracellular trafficking of β-glucosidase in different human cellular models.
abstract: Acid β-glucosidase (GCase), the enzyme deficient in Gaucher disease (GD), is transported to lysosomes by the lysosomal integral membrane protein (LIMP)-2. In humans, LIMP-2 deficiency leads to action myoclonus-renal failure (AMRF) syndrome. GD and AMRF syndrome share some clinical features. However, they are different from clinical and biochemical points of view, suggesting that the role of LIMP-2 in the targeting of GCase would be different in different tissues. Besides, the role of LIMP-2 in the uptake and trafficking of the human recombinant (hr)GCase used in the treatment of GD is unknown. Thus, we compared GCase activity and intracellular localization in immortalized lymphocytes, fibroblasts, and a neuronal model derived from multipotent adult stem cells, from a patient with AMRF syndrome, patients with GD, and control subjects. In fibroblasts and neuronlike cells, GCase targeting to the lysosomes is completely dependent on LIMP-2, whereas in blood cells, GCase is partially targeted to lysosomes by a LIMP-2-independent mechanism. Although hrGCase cellular uptake is independent of LIMP-2, its trafficking to the lysosomes is mediated by this receptor. These data provide new insights into the mechanisms involved in the intracellular trafficking of GCase and in the pathogeneses of GD and AMRF syndrome.
authors.affiliation: Regional Coordinator Centre for Rare Diseases, University Hospital Santa Maria della Misericordia, Udine, Italy.
authors.forename: Erika
authors.initials: E
authors.lastname: Malini
authors.affiliation: Regional Coordinator Centre for Rare Diseases, University Hospital Santa Maria della Misericordia, Udine, Italy.
authors.forename: Stefania
authors.initials: S
authors.lastname: Zampieri
authors.affiliation: Regional Coordinator Centre for Rare Diseases, University Hospital Santa Maria della Misericordia, Udine, Italy.
authors.forename: Marta
authors.initials: M
authors.lastname: Deganuto
authors.affiliation: Regional Coordinator Centre for Rare Diseases, University Hospital Santa Maria della Misericordia, Udine, Italy.
authors.forename: Milena
authors.initials: M
authors.lastname: Romanello
authors.affiliation: Regional Coordinator Centre for Rare Diseases, University Hospital Santa Maria della Misericordia, Udine, Italy.
authors.forename: Annalisa
authors.initials: A
authors.lastname: Sechi
authors.affiliation: Regional Coordinator Centre for Rare Diseases, University Hospital Santa Maria della Misericordia, Udine, Italy.
authors.forename: Bruno
authors.initials: B
authors.lastname: Bembi
authors.affiliation: Regional Coordinator Centre for Rare Diseases, University Hospital Santa Maria della Misericordia, Udine, Italy dardis.andrea@aoud.sanita.fvg.it.
authors.forename: Andrea
authors.initials: A
authors.lastname: Dardis
mesh_terms: D000328:Adult; D053687:Adult Stem Cells / Q000378:metabolism* / Q000473:pathology; D005347:Fibroblasts / Q000378:metabolism* / Q000473:pathology; D005962:Glucosylceramidase / Q000493:pharmacokinetics / Q000494:pharmacology; D006801:Humans; D008214:Lymphocytes / Q000378:metabolism* / Q000473:pathology; D051907:Lysosomal Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D008247:Lysosomes / Q000378:metabolism / Q000473:pathology; D039902:Multipotent Stem Cells / Q000378:metabolism* / Q000473:pathology; D020191:Myoclonic Epilepsies, Progressive / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D021381:Protein Transport / Q000187:drug effects / Q000235:genetics; D051116:Receptors, Scavenger / Q000235:genetics / Q000378:metabolism*; D011994:Recombinant Proteins / Q000493:pharmacokinetics / Q000494:pharmacology
chemical_list: D051907:Lysosomal Membrane Proteins; D051116:Receptors, Scavenger; D011994:Recombinant Proteins; C074299:SCARB2 protein, human; D005962:Glucosylceramidase
keywords: AMRF syndrome; Gaucher disease; lysosomal disease