Decreased canonical Wnt signaling is a hallmark of impaired lysosomal function in a fish model for Gaucher disease

The lysosome is the final destination compartment to which the content of multivesicular endosomes (MVEs) release their content. Many target proteins, including the Wnt signaling modulator, Glycogen-synthase-kinase 3 (GSK3), have been tightly associated with the activity of MVEs, so that upon Wnt ligand binding to its receptors, GSK3 is sequestered into the MVEs. How a deficient lysosomal function could be related to altered Wnt signaling has never been elucidated before. Type I Gaucher disease (GD; OMIM #230800) is caused by mutations in the gene encoding the lysosomal enzyme glucocerebrosidase (GBA1). Impaired enzymatic activity leads to considerable lysosomal amassment of undegraded glucocerebroside (GC) and a subsequent massive inflammatory response. However, accumulation of uncleaved GC is limited to few cell types and does not explain major organ abnormalities. Using a morpholino-based GBA knockdown approach and an available genetic mutant we have analyzed the effects of GBA loss of function on different cell signaling pathways. Our results suggest that the impaired GBA function leads to canonical Wnt signaling activity decrease, which in turn severely affect fish osteogenesis. These observations establish a new paradigm in the pathogenesis of Gaucher disease and define a possible relation of lysosomal compartment function and the Wnt signaling pathway.