Ablation of the pro-inflammatory master regulator miR-155 does not mitigate neuroinflammation or neurodegeneration in a vertebrate model of Gaucher's disease
Bi-allelic mutations in the glucocerebrosidase gene (GBA1) cause Gaucher's disease, the most common human
lysosomal storage disease. We previously reported a marked increase in miR-155 transcript levels and early
microglial activation in a zebrafish model of Gaucher's disease (gba1−/−). miR-155 is a master regulator of
inflammation and has been implicated in a wide range of different neurodegenerative disorders. The observed
miR-155 upregulation preceded the subsequent development of widespread pathology with marked neuroinflammation, closely resembling human Gaucher's disease pathology. We now report similar increases of miR-155
expression in mammalian models of GD, confirming that miR-155 upregulation is a shared feature in glucocerebrosidase (GCase) deficiency across different species. Using CRISPR/Cas9 mutagenesis we then generated a
miR-155 mutant zebrafish line (miR-155−/−) with completely abolished miR-155 expression. Unexpectedly, loss
of miR-155 did not mitigate either the reduced lifespan or the robust inflammatory phenotypes of gba1−/−
mutant zebrafish. Our data demonstrate that neither neuroinflammation nor disease progression in GCase deficiency are dependent on miR-155 and suggest that miR-155 inhibition would not be a promising therapeutic
target in Gaucher's disease