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: Elma Aflaki, Barbara K Stubblefield, Emerson Maniwang, Grisel Lopez, Nima Moaven, Ehud Goldin, Juan Marugan, Samarjit Patnaik, Amalia Dutra, Noel Southall, Wei Zheng, Nahid Tayebi, Ellen Sidransky
• Journal: Science translational medicine (Sci Transl Med) Vol. 6 Issue 240 Pg. 240ra73 (Jun 11 2014) ISSN: 1946-6242 [Electronic] United States
• PMID: 24920659 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, N.I.H., Intramural)
• Copyright: Copyright © 2014, American Association for the Advancement of Science.

Chemical References

• Glucosylceramides
• Psychosine
• sphingosyl beta-glucoside
• Glucosylceramidase

Topics

• Cells, Cultured
• Gaucher Disease (metabolism, pathology)
• Glucosylceramidase (metabolism)
• Glucosylceramides (metabolism)
• Humans
• Induced Pluripotent Stem Cells (cytology)
• Lysosomes (metabolism)
• Macrophages (cytology, metabolism)
• Monocytes (metabolism)
• Psychosine (analogs & derivatives, metabolism)