Glucocerebrosidase gene-deficient mouse recapitulates gaucher disease displaying cellular and molecular dysregulation beyond the macrophage

Pramod K. Mistrya, Jun Liua, Mei Yanga, Timothy Nottolic, James McGratha, Dhanpat Jaine, Kate Zhangf, Joan Keutzerf, Wei Lein Chuangf, Wajahat Z. Mehalb, Hongyu Zhaog, Aiping Lin, Shrikant Maneh, Xuan Liu, Yuan Z. Peng, Jian H. Li, Manasi Agrawal, Ling Ling Zhu, Harry C. Blair, Lisa J. RobinsonJameel Iqbal, Li Sun, Mone Zaidi

Research output: Contribution to journalArticlepeer-review

190 Scopus citations

Abstract

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.

Original languageEnglish
Pages (from-to)19473-19478
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume107
Issue number45
DOIs
StatePublished - 9 Nov 2010

Keywords

  • Glucosylsphingosine
  • Osteoblast
  • Osteopenia
  • PKC
  • T cells

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