title: Glucocerebrosidase 2 gene deletion rescues type 1 Gaucher disease.
abstract: The inherited deficiency of the lysosomal glucocerebrosidase (GBA) due to mutations in the GBA gene results in Gaucher disease (GD). A vast majority of patients present with nonneuronopathic, type 1 GD (GD1). GBA deficiency causes the accumulation of two key sphingolipids, glucosylceramide (GL-1) and glucosylsphingosine (LysoGL-1), classically noted within the lysosomes of mononuclear phagocytes. How metabolites of GL-1 or LysoGL-1 produced by extralysosomal glucocerebrosidase GBA2 contribute to the GD1 pathophysiology is not known. We recently recapitulated hepatosplenomegaly, cytopenia, hypercytokinemia, and the bone-formation defect of human GD1 through conditional deletion of Gba in Mx1-Cre(+):GD1 mice. Here we show that the deletion of Gba2 significantly rescues the GD1 clinical phenotype, despite enhanced elevations in GL-1 and LysoGL-1. Most notably, the reduced bone volume and bone formation rate are normalized. These results suggest that metabolism of GL-1 or LysoGL-1 into downstream bioactive lipids is a major contributor to the bone-formation defect. Direct testing revealed a strong inhibition of osteoblast viability by nanomolar concentrations of sphingosine, but not of ceramide. These findings are consistent with toxicity of high circulating sphingosine levels in GD1 patients, which decline upon enzyme-replacement therapy; serum ceramide levels remain unchanged. Together, complementary results from mice and humans affected with GD1 not only pinpoint sphingosine as being an osteoblast toxin, but also set forth Gba2 as a viable therapeutic target for the development of inhibitors to ameliorate certain disabling consequences of GD1.
authors.affiliation: Department of Medicine, Yale School of Medicine, New Haven, CT 06520.
authors.forename: Pramod K
authors.initials: PK
authors.lastname: Mistry
authors.forename: Jun
authors.initials: J
authors.lastname: Liu
authors.forename: Li
authors.initials: L
authors.lastname: Sun
authors.forename: Wei-Lien
authors.initials: WL
authors.lastname: Chuang
authors.forename: Tony
authors.initials: T
authors.lastname: Yuen
authors.forename: Ruhua
authors.initials: R
authors.lastname: Yang
authors.forename: Ping
authors.initials: P
authors.lastname: Lu
authors.forename: Kate
authors.initials: K
authors.lastname: Zhang
authors.forename: Jianhua
authors.initials: J
authors.lastname: Li
authors.forename: Joan
authors.initials: J
authors.lastname: Keutzer
authors.forename: Agnes
authors.initials: A
authors.lastname: Stachnik
authors.forename: Albert
authors.initials: A
authors.lastname: Mennone
authors.forename: James L
authors.initials: JL
authors.lastname: Boyer
authors.forename: Dhanpat
authors.initials: D
authors.lastname: Jain
authors.forename: Roscoe O
authors.initials: RO
authors.lastname: Brady
authors.forename: Maria I
authors.initials: MI
authors.lastname: New
authors.forename: Mone
authors.initials: M
authors.lastname: Zaidi
mesh_terms: D000818:Animals; D002460:Cell Line; D005776:Gaucher Disease / Q000201:enzymology / Q000235:genetics* / Q000628:therapy*; D017353:Gene Deletion; D006801:Humans; D053858:Metabolic Networks and Pathways; D051379:Mice; D008810:Mice, Inbred C57BL; D010006:Osteoblasts / Q000378:metabolism / Q000473:pathology; D010641:Phenotype; D013107:Sphingolipids / Q000378:metabolism; D013110:Sphingosine / Q000378:metabolism; D001617:beta-Glucosidase / Q000235:genetics*
chemical_list: D013107:Sphingolipids; D001617:beta-Glucosidase; C517538:beta-glucosidase 2, mouse; D013110:Sphingosine
keywords: S1P; knockout mice; macrophage