Editors' ChoiceLysosomal Storage Diseases

New Cellular Culprits in Gaucher's Disease

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Science Translational Medicine  10 Nov 2010:
Vol. 2, Issue 57, pp. 57ec174
DOI: 10.1126/scitranslmed.3001883

Type 1 Gaucher's disease (GD1) is caused by defects in the enzyme glucocerebrosidase (GBA1). This results in accumulation of the glycolipid glucocerebroside in the lysosomes principally of macrophages. Patients with GD1 suffer from a wide variety of symptoms including enlarged spleen, liver, and lymph nodes, as well as defects in the immune system, anemia, and loss of bone mass (osteopenia). Successful bone marrow transplantation alleviates most of the symptoms of GD1 but does not normalize bone mass. The current view of this disease is a macrophage-centric one, yet there are puzzling symptoms—such as pulmonary hypertension, Parkinson's disease, and an increased risk of cancer—that cannot be explained by defective macrophages alone. Mistry et al. investigate this puzzle further by engineering a new mouse model of GD1. They demonstrate that macrophages do not act alone in this disease but have osteoblasts, dendritic cells, and T cells as accomplices.

To engineer their GD1 mice, the authors deleted the GBA1 gene only in cells of the hematopoietic and mesenchymal lineages. These mice exhibited many of the symptoms of the human disease, including profound osteopenia. The investigators discovered that the osteopenia was caused by a defect in bone formation. They show that glucocerebroside blocks protein kinase C signaling in osteoblasts, cells of the mesenchymal lineage that build up bone. Next, they demonstrate that other cell types were also affected in the GD1 mice such as T cells and dendritic cells of the immune system. However, cells such as osteoclasts that resorb bone and are derived from the same lineage as macrophages were unaffected. These findings reveal that GD1 is not just a disease of macrophages but involves other cell types as well, accounting for the wide variety of symptoms observed. Of course, it is possible that these other cells are impaired indirectly due to loss of paracrine signals from macrophages. The new GD1 mouse model engineered by Mistry et al. will enable future studies to dissect the role of GBA1 in nonmacrophage cell types, leading to a more comprehensive understanding of this disease.

P. K. Mistry et al., Glucocerebrosidase gene-deficient mouse recapitulates Gaucher disease displaying cellular and molecular dysregulation beyond the macrophage. Proc. Natl. Acad. Sci. U.S.A., 20 October 2010 (10.1073/pnas.1003308107). [Abstract]

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