Abstract
Gaucher Disease (GD), which is the most common lysosomal storage disorder, is caused by bi-allelic mutations in GBA1—a gene that encodes the lysosomal hydrolase β-glucocerebrosidase (GCase). The neuronopathic forms of GD (nGD) are characterized by severe neurological abnormalities that arise during gestation or early in infancy. Using GD-induced pluripotent stem cell (iPSC)-derived neuronal progenitor cells (NPCs), we have previously reported that neuronal cells have neurodevelopmental defects associated with the downregulation of canonical Wnt signaling. In this study, we report that GD NPCs display elevated levels of Dkk1, which is a secreted Wnt antagonist that prevents receptor activation. Dkk1 upregulation in mutant NPCs resulted in an increased degradation of β-catenin, and there was a concomitant reduction in lysosomal numbers. Consistent with these results, incubation of the mutant NPCs with recombinant Wnt3a (rWnt3a) was able to outcompete the excess Dkk1, increasing β-catenin levels and rescuing lysosomal numbers. Furthermore, the incubation of WT NPCs with recombinant Dkk1 (rDkk1) phenocopied the mutant phenotype, recapitulating the decrease in β-catenin levels and lysosomal depletion seen in nGD NPCs. This study provides evidence that downregulation of the Wnt/β-catenin pathway in nGD neuronal cells involves the upregulation of Dkk1. As Dkk1 is an extracellular Wnt antagonist, our results suggest that the deleterious effects of Wnt/β-catenin downregulation in nGD may be ameliorated by the prevention of Dkk1 binding to the Wnt co-receptor LRP6, pointing to Dkk1 as a potential therapeutic target for GBA1-associated neurodegeneration.
Highlights
Gaucher Disease (GD) is an autosomal recessive disease caused by monogenic mutations in the GBA1 gene
We have previously shown that GBA1 mutations downregulate the Wnt/β-catenin pathway in neuronopathic forms of GD (nGD) induced pluripotent stem cell (iPSC)-derived neuronal progenitor cells (NPCs)
We report that Dkk1 plays a key role in downregulation of the canonical Wnt pathway in nGD iPSC-derived NPCs, and that Wnt downregulation interferes with the lysosomal function
Summary
Gaucher Disease (GD) is an autosomal recessive disease caused by monogenic mutations in the GBA1 gene. Mutations in GBA1 affect GCase protein folding, resulting in endoplasmic reticulum retention and subsequent degradation [1,2]. GD patients have varied onsets and severities of clinical manifestations, with a poor correlation between the genotype and phenotype [6,7]. Patients with neuronopathic subtypes (type 2 and type 3 GD) display severe neurological manifestations, including neurodegeneration, neuronal loss, ataxia, myoclonic seizures, and other abnormalities [8,9,10,11,12,13,14,15]. The rapid progression of the disease in type 2 GD (GD2) patients results in death within two years of age, while patients with type 3 GD (GD3) exhibit a slower clinical course [16,17,18]. Mutations in GBA1 are the most common genetic risk factor for Parkinson’s disease (PD), with a 5–20 fold increased risk of developing PD in GD patients or carriers of GBA1 mutations [19,20,21,22,23,24]
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