title: A Comparative Study on the Alterations of Endocytic Pathways in Multiple Lysosomal Storage Disorders.
abstract: Many cellular activities and pharmaceutical interventions involve endocytosis and delivery to lysosomes for processing. Hence, lysosomal processing defects can cause cell and tissue damage, as in lysosomal storage diseases (LSDs) characterized by lysosomal accumulation of undegraded materials. This storage causes endocytic and trafficking alterations, which exacerbate disease and hinder treatment. However, there have been no systematic studies comparing different endocytic routes in LSDs. Here, we used genetic and pharmacological models of four LSDs (type A Niemann-Pick, type C Niemann-Pick, Fabry, and Gaucher diseases) and evaluated the pinocytic and receptor-mediated activity of the clathrin-, caveolae-, and macropinocytic routes. Bulk pinocytosis was diminished in all diseases, suggesting a generic endocytic alteration linked to lysosomal storage. Fluid-phase (dextran) and ligand (transferrin) uptake via the clathrin route were lower for all LSDs. Fluid-phase and ligand (cholera toxin B) uptake via the caveolar route were both affected but less acutely in Fabry or Gaucher diseases. Epidermal growth factor-induced macropinocytosis was altered in Niemann-Pick cells but not other LSDs. Intracellular trafficking of ligands was also distorted in LSD versus wild-type cells. The extent of these endocytic alterations paralleled the level of cholesterol storage in disease cell lines. Confirming this, pharmacological induction of cholesterol storage in wild-type cells disrupted endocytosis, and model therapeutics restored uptake in proportion to their efficacy in attenuating storage. This suggests a proportional and reversible relationship between endocytosis and lipid (cholesterol) storage. By analogy, the accumulation of biological material in other diseases, or foreign material from drugs or their carriers, may cause similar deficits, warranting further investigation.
authors.affiliation: Fischell Department of Bioengineering, University of Maryland, College Park, MD 20742-4450, USA.
authors.forename: Jeff
authors.initials: J
authors.lastname: Rappaport
authors.affiliation: Fischell Department of Bioengineering, University of Maryland, College Park, MD 20742-4450, USA.
authors.forename: Rachel L
authors.initials: RL
authors.lastname: Manthe
authors.affiliation: Institute for Bioscience and Biotechnology Research, University of Maryland, 5115 Plant Sciences Building, College Park, MD 20742-4450, USA.
authors.forename: Melani
authors.initials: M
authors.lastname: Solomon
authors.affiliation: Department of Normal and Pathological Histology and Cytology, University of Seville School of Medicine, Seville 41009, Spain.
authors.forename: Carmen
authors.initials: C
authors.lastname: Garnacho
authors.affiliation: Fischell Department of Bioengineering, University of Maryland, College Park, MD 20742-4450, USA.|Institute for Bioscience and Biotechnology Research, University of Maryland, 5115 Plant Sciences Building, College Park, MD 20742-4450, USA.
authors.forename: Silvia
authors.initials: S
authors.lastname: Muro
mesh_terms: D001692:Biological Transport; D002784:Cholesterol / Q000378:metabolism*; D002966:Clathrin / Q000378:metabolism; D004705:Endocytosis / Q000502:physiology*; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology; D005776:Gaucher Disease / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D008055:Lipids / Q000737:chemistry*; D016464:Lysosomal Storage Diseases / Q000378:metabolism* / Q000473:pathology; D008247:Lysosomes / Q000378:metabolism*; D008855:Microscopy, Electron, Scanning; D009542:Niemann-Pick Diseases / Q000378:metabolism* / Q000473:pathology; D010873:Pinocytosis / Q000502:physiology; D012867:Skin / Q000378:metabolism / Q000473:pathology
chemical_list: D002966:Clathrin; D008055:Lipids; D018799:Intercellular Adhesion Molecule-1; D002784:Cholesterol
keywords: ICAM-1-targeted nanocarriers; endocytosis pathways; enzyme replacement therapy; lysosomal storage diseases; lysosomal storage reduction