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.macrophage | knockout mice | S1P

Unexpected macrophage-independent dyserythropoiesis in Gaucher disease

“…10,24 The results of the study herein do not permit a conclusion as to whether the dyserythropoiesis is directly due to the reduced enzyme activity and lipid accumulation, or to an alteration in the mechanisms involved in enzyme folding. Alternatively, since sphingosine 1-phosphate (S1P), as a bioactive lipid, can affect the hematopoiesis and RBC signaling in addition to its multiple cellular and systemic functions, [40][41][42] the possibility that the abnormal sphingolipid contents in the erythroid progenitors could affect erythropoiesis could be an interesting hypothesis to investigate.…”

“…9,10 We previously detected GCerase activity in normal erythroblasts but not in circulating RBCs. 11 High lipid levels have been frequently reported in the plasma and RBCs of GD patients, [22][23][24][25] which raises the possibility that the RBCs are overloaded with lipids due to the passive incorporation of GlcCer and/or that the erythroid progenitors are primarily affected. To evaluate the alterations in the erythroid progenitors, we performed in vitro experiments to study the erythroid differentiation from peripheral blood samples from GD type 1 patients.…”

Lack of enzyme activity in GBA2 mutants associated with hereditary spastic paraplegia/cerebellar ataxia (SPG46)

“…It is not understood why the Gba2-deficient mice do not develop ataxia or paraplegia. Moreover, ablation of the Gba2 gene lessens the disease severity of a mouse model for type 1 Gaucher disease disease, by lowering cytokine levels and normalizing bone volume [15].…”

Doença De Gaucher Tipo 1 No Esqueleto: Revisão Da América Latina

“…Overall, we can substantiate the fact that there is either no change, or a decrease in osteoblast proliferation, in conjunction with either no change or an increase in osteoclast proliferation. 20,[25][26][27] Prevalence of bone manifestations in Latin American GD1 patients ICGG Gaucher Registry (current)…”