| Summary: | Human <i>GBA1</i> encodes lysosomal acid β-glucocerebrosidase (GCase), which hydrolyzes cleavage of the beta-glucosidic linkage of glucosylceramide (GlcCer). Mutations in this gene lead to reduced GCase activity, accumulation of glucosylceramide and glucosylsphingosine, and development of Gaucher disease (GD). <i>Drosophila melanogaster</i> has two <i>GBA1</i> orthologs. Thus far, <i>GBA1b</i> was documented as a <i>bone fide</i> GCase-encoding gene, while the role of <i>GBA1a</i> encoded protein remained unclear. In the present study, we characterized a mutant variant of the fly <i>GBA1a</i>, which underwent ERAD and mildly activated the UPR machinery. RNA-seq analyses of homozygous mutant flies revealed upregulation of inflammation-associated as well as of cell-cycle related genes and reduction in programmed cell death (PCD)-associated genes, which was confirmed by qRT-PCR. We also observed compromised cell death in the midgut of homozygous larvae and a reduction in pupation. Our results strongly indicated that <i>GBA1a</i>-encoded protein plays a role in midgut maturation during larvae development.
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