The Uncovered Function of the Drosophila GBA1a-Encoded Protein

Area of Science:

• Genetics
• Developmental Biology
• Biochemistry

Background:

• Human GBA1 mutations cause Gaucher disease by impairing lysosomal acid beta-glucocerebrosidase (GCase).
• Drosophila melanogaster possesses two GBA1 orthologs, GBA1a and GBA1b, with GBA1b previously identified as the functional GCase gene.
• The specific function of the GBA1a-encoded protein remained largely uncharacterized.

Purpose of the Study:

• To investigate the function of the Drosophila GBA1a-encoded protein.
• To characterize the effects of GBA1a mutations on fly development and cellular processes.

Main Methods:

• Characterization of a mutant GBA1a variant exhibiting ER-associated degradation (ERAD) and mild UPR activation.
• RNA-sequencing (RNA-seq) analysis of homozygous mutant flies.
• Quantitative reverse transcription PCR (qRT-PCR) for gene expression validation.
• Assessment of cell death in larval midguts and pupation rates.

Main Results:

• Mutant GBA1a underwent ERAD and mildly activated the unfolded protein response (UPR).
• RNA-seq revealed upregulation of inflammation and cell-cycle genes, and downregulation of programmed cell death (PCD) genes.
• Homozygous mutant larvae showed compromised midgut cell death and reduced pupation success.
• GBA1a deficiency impacted midgut maturation during larval development.

Conclusions:

• The GBA1a-encoded protein plays a significant role in Drosophila larval midgut maturation.
• GBA1a influences programmed cell death and cell-cycle regulation during development.
• These findings expand the known functions associated with GBA1 orthologs beyond canonical GCase activity.