GBA1 MUTATIONS INTERFERE WITH WNT/β-CATENIN SIGNALING AND LINEAGE DIFFERENTIATION IN GAUCHER IPSC-DERIVED NEURONAL PROGENITORS. Robert Liu*, Ola Awad, and Ricardo Feldman, Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, MD.
Gaucher disease (GD) is an inherited lipid-storage disease caused by mutations in the acid beta-glucocerebrosidase gene (GBA1). Mutant glucocerebrosidase (GCase) leads to the accumulation of glucosylceramide and neurotoxic metabolites. In types 1, 2, and 3 GD, sphingolipid accumulation in macrophages leads to hepatosplenomegaly, hematologic abnormalities, and bone disease. In the severe types 2 and 3 GD, there are also serious neurological manifestations. Using iPSCs, we previously found that GD causes canonical Wnt/β-catenin …show more content…
As canonical Wnt signaling regulates NPC heterogeneity and regional identity, we suspect that neuronopathic GD mutations will accordingly affect other neuronal lineages in a Wnt-dependent manner. In order to understand the functional relation between Wnt downregulation and neurodegeneration, we analyzed GD NPCs for the presence of regional markers characteristic of forebrain (FoxG1, TBR1, OTX2), midbrain (NURR1, LMX1A) and hindbrain (HoxB4, MNX1). This was done by a combination of immunofluorescence and immunoblot analysis. Our results showed that GD has little effect on forebrain NPCs but causes significant depletion of midbrain and hindbrain NPCs, suggesting that the neurodevelopmental abnormalities in GD neuronal progenitors are likely due to deregulation of the Wnt pathway. Immunoblot analysis demonstrated that FoxG1 and TBR1 levels were approximately equal in control and GD NPCs, while HoxB4
Gaucher disease (GD) is an inherited lipid-storage disease caused by mutations in the acid beta-glucocerebrosidase gene (GBA1). Mutant glucocerebrosidase (GCase) leads to the accumulation of glucosylceramide and neurotoxic metabolites. In types 1, 2, and 3 GD, sphingolipid accumulation in macrophages leads to hepatosplenomegaly, hematologic abnormalities, and bone disease. In the severe types 2 and 3 GD, there are also serious neurological manifestations. Using iPSCs, we previously found that GD causes canonical Wnt/β-catenin …show more content…
As canonical Wnt signaling regulates NPC heterogeneity and regional identity, we suspect that neuronopathic GD mutations will accordingly affect other neuronal lineages in a Wnt-dependent manner. In order to understand the functional relation between Wnt downregulation and neurodegeneration, we analyzed GD NPCs for the presence of regional markers characteristic of forebrain (FoxG1, TBR1, OTX2), midbrain (NURR1, LMX1A) and hindbrain (HoxB4, MNX1). This was done by a combination of immunofluorescence and immunoblot analysis. Our results showed that GD has little effect on forebrain NPCs but causes significant depletion of midbrain and hindbrain NPCs, suggesting that the neurodevelopmental abnormalities in GD neuronal progenitors are likely due to deregulation of the Wnt pathway. Immunoblot analysis demonstrated that FoxG1 and TBR1 levels were approximately equal in control and GD NPCs, while HoxB4