title: Macrophage models of Gaucher disease for evaluating disease pathogenesis and candidate drugs.
abstract: Gaucher disease is caused by an inherited deficiency of glucocerebrosidase that manifests with storage of glycolipids in lysosomes, particularly in macrophages. Available cell lines modeling Gaucher disease do not demonstrate lysosomal storage of glycolipids; therefore, we set out to develop two macrophage models of Gaucher disease that exhibit appropriate substrate accumulation. We used these cellular models both to investigate altered macrophage biology in Gaucher disease and to evaluate candidate drugs for its treatment. We generated and characterized monocyte-derived macrophages from 20 patients carrying different Gaucher disease mutations. In addition, we created induced pluripotent stem cell (iPSC)-derived macrophages from five fibroblast lines taken from patients with type 1 or type 2 Gaucher disease. Macrophages derived from patient monocytes or iPSCs showed reduced glucocerebrosidase activity and increased storage of glucocerebroside and glucosylsphingosine in lysosomes. These macrophages showed efficient phagocytosis of bacteria but reduced production of intracellular reactive oxygen species and impaired chemotaxis. The disease phenotype was reversed with a noninhibitory small-molecule chaperone drug that enhanced glucocerebrosidase activity in the macrophages, reduced glycolipid storage, and normalized chemotaxis and production of reactive oxygen species. Macrophages differentiated from patient monocytes or patient-derived iPSCs provide cellular models that can be used to investigate disease pathogenesis and facilitate drug development.
authors.affiliation: Section on Molecular Neurogenetics, Medical Genetics Branch, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Elma
authors.initials: E
authors.lastname: Aflaki
authors.affiliation: Section on Molecular Neurogenetics, Medical Genetics Branch, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Barbara K
authors.initials: BK
authors.lastname: Stubblefield
authors.affiliation: Section on Molecular Neurogenetics, Medical Genetics Branch, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Emerson
authors.initials: E
authors.lastname: Maniwang
authors.affiliation: Section on Molecular Neurogenetics, Medical Genetics Branch, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Grisel
authors.initials: G
authors.lastname: Lopez
authors.affiliation: Section on Molecular Neurogenetics, Medical Genetics Branch, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Nima
authors.initials: N
authors.lastname: Moaven
authors.affiliation: Section on Molecular Neurogenetics, Medical Genetics Branch, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Ehud
authors.initials: E
authors.lastname: Goldin
authors.affiliation: National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Rockville, MD 20850, USA.
authors.forename: Juan
authors.initials: J
authors.lastname: Marugan
authors.affiliation: National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Rockville, MD 20850, USA.
authors.forename: Samarjit
authors.initials: S
authors.lastname: Patnaik
authors.affiliation: Cytogenetics and Microscopy Core, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Amalia
authors.initials: A
authors.lastname: Dutra
authors.affiliation: National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Rockville, MD 20850, USA.
authors.forename: Noel
authors.initials: N
authors.lastname: Southall
authors.affiliation: National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Rockville, MD 20850, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Zheng
authors.affiliation: Section on Molecular Neurogenetics, Medical Genetics Branch, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Nahid
authors.initials: N
authors.lastname: Tayebi
authors.affiliation: Section on Molecular Neurogenetics, Medical Genetics Branch, National Institutes of Health, Bethesda, MD 20892, USA. sidranse@mail.nih.gov.
authors.forename: Ellen
authors.initials: E
authors.lastname: Sidransky
mesh_terms: D002478:Cells, Cultured; D005776:Gaucher Disease / Q000378:metabolism* / Q000473:pathology*; D005962:Glucosylceramidase / Q000378:metabolism; D005963:Glucosylceramides / Q000378:metabolism; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000166:cytology; D008247:Lysosomes / Q000378:metabolism; D008264:Macrophages / Q000166:cytology / Q000378:metabolism*; D009000:Monocytes / Q000378:metabolism; D011609:Psychosine / Q000031:analogs & derivatives / Q000378:metabolism
chemical_list: D005963:Glucosylceramides; D011609:Psychosine; C035742:sphingosyl beta-glucoside; D005962:Glucosylceramidase