The Uncovered Function of the Drosophila GBA1a-Encoded Protein.

Or Cabasso,Johannes Aerts,Mia Horowitz,Gali Maor,Metsada Pasmanik-Chor,Wouter Kallemeijn,Sumit Paul

doi:10.3390/cells10030630

Or Cabasso, Johannes Aerts + Show 5 more

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https://doi.org/10.3390/cells10030630

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Abstract

Human GBA1 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). Drosophila melanogaster has two GBA1 orthologs. Thus far, GBA1b was documented as a bone fide GCase-encoding gene, while the role of GBA1a encoded protein remained unclear. In the present study, we characterized a mutant variant of the fly GBA1a, 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 GBA1a-encoded protein plays a role in midgut maturation during larvae development.

Highlights

Human acid β-glucocerebrosidase (GCase) is encoded by the GBA1 gene, mutations in which lead to reduced GCase activity, accumulation of glucosylceramide (GlcCer) and glucosylsphingosine (GlcSph), and development of Gaucher disease (GD)
While expression of GBA1a is mostly restricted to bodies, GBA1b mRNA is the major species expressed in heads (FlyBase.org) [3,4,5]
Our results indicated that mutant GBA1a-encoded protein mildly activated UPR, upregulated inflammation, and downregulated programmed cell death (PCD)-related genes, which culminated in retarded midgut maturation during early pupation

Summary

Introduction

Human acid β-glucocerebrosidase (GCase) is encoded by the GBA1 gene, mutations in which lead to reduced GCase activity, accumulation of glucosylceramide (GlcCer) and glucosylsphingosine (GlcSph), and development of Gaucher disease (GD). In Drosophila, there are two GBA1 orthologs, GBA1a (CG31148) and GBA1b (CG31414); both are located on chromosome 3. They are ~2 Kb (3R: 23,700,621–23,702,605) and ~4 Kb in size (3R: 23,704,804–23,708,512), respectively, and are separated by a non-relevant gene (CG31413) (FlyBase.org). The sequences of GBA1a and GBA1b encoded proteins share ~50% similarity with the human GCase, and the two catalytic amino acids, which determine GCase activity, are identical between human GCase and fly GBA1a and GBA1b proteins (E235 and E340 in human GCase [2], E298 and E405 in both fly GBA1-encoded proteins). While expression of GBA1a is mostly restricted to bodies, GBA1b mRNA is the major species expressed in heads (FlyBase.org) [3,4,5]

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