The Uncovered Function of the <i>Drosophila GBA1a</i>-Encoded Protein

• Main Authors: Or Cabasso, Sumit Paul, Gali Maor, Metsada Pasmanik-Chor, Wouter Kallemeijn, Johannes Aerts, Mia Horowitz
• Format: Article
• Language: English
• Published: MDPI AG 2021-03-01
• Series: Cells
• Subjects: <i>GBA1</i>; acid β-glucocerebrosidase; Gaucher disease; unfolded protein response; inflammation
• Online Access: https://www.mdpi.com/2073-4409/10/3/630

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.