Open AccessGlucocerebrosidase gene-deficient mouse recapitulates Gaucher disease displaying cellular and molecular dysregulation beyond the macrophage
Author(s) -
Pramod K. Mistry,
Jun Li,
Mei Yang,
Timothy Nottoli,
James McGrath,
Dhanpat Jain,
Kate Zhang,
Joan Keutzer,
Wei-Lien Chuang,
Wajahat Z. Mehal,
Hongyu Zhao,
Lin Ai,
Shrikant Mane,
Xuan Li,
Yuan Peng,
Jian H. Li,
Manasi Agrawal,
Lijing Zhu,
Harry C. Blair,
Lisa J. Robinson,
Jameel Iqbal,
Li Sun,
Mone Zaidi
Publication year - 2010
Publication title -
proceedings of the national academy of sciences of the united states of america
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.011
H-Index - 771
eISSN - 1091-6490
pISSN - 0027-8424
DOI - 10.1073/pnas.1003308107
Subject(s) - glucocerebrosidase , glucocerebroside , gaucher's disease , biology , macrophage , haematopoiesis , cancer research , microbiology and biotechnology , immunology , disease , gene , medicine , pathology , stem cell , genetics , in vitro
In nonneuronopathic type 1 Gaucher disease (GD1), mutations in the glucocerebrosidase gene (GBA1) gene result in glucocerebrosidase deficiency and the accumulation of its substrate, glucocerebroside (GL-1), in the lysosomes of mononuclear phagocytes. This prevailing macrophage-centric view, however, does not explain emerging aspects of the disease, including malignancy, autoimmune disease, Parkinson disease, and osteoporosis. We conditionally deleted the GBA1 gene in hematopoietic and mesenchymal cell lineages using an Mx1 promoter. Although this mouse fully recapitulated human GD1, cytokine measurements, microarray analysis, and cellular immunophenotyping together revealed widespread dysfunction not only of macrophages, but also of thymic T cells, dendritic cells, and osteoblasts. The severe osteoporosis was caused by a defect in osteoblastic bone formation arising from an inhibitory effect of the accumulated lipids LysoGL-1 and GL-1 on protein kinase C. This study provides direct evidence for the involvement in GD1 of multiple cell lineages, suggesting that cells other than macrophages may be worthwhile therapeutic targets.