Drosophila melanogaster Mutated in its GBA1b Ortholog Recapitulates Neuronopathic Gaucher Disease

Abstract

Gaucher disease (GD) results from mutations in the GBA1 gene, which encodes lysosomal glucocerebrosidase (GCase). The large number of mutations known to date in the gene lead to a heterogeneous disorder, which is divided into a non-neuronopathic, type 1 GD, and two neurological, type 2 and type 3, forms. We studied the two fly GBA1 orthologs, GBA1a and GBA1b. Each contains a Minos element insertion, which truncates its coding sequence. In the GBA1am/m flies, which express a mutant protein, missing 33 C-terminal amino acids, there was no decrease in GCase activity or substrate accumulation. However, GBA1bm/m mutant flies presented a significant decrease in GCase activity with concomitant substrate accumulation, which included C14:1 glucosylceramide and C14:0 glucosylsphingosine. GBA1bm/m mutant flies showed activation of the Unfolded Protein Response (UPR) and presented inflammation and neuroinflammation that culminated in development of a neuronopathic disease. Treatment with ambroxol did not rescue GCase activity or reduce substrate accumulation; however, it ameliorated UPR, inflammation and neuroinflammation, and increased life span. Our results highlight the resemblance between the phenotype of the GBA1bm/m mutant fly and neuronopathic GD and underlie its relevance in further GD studies as well as a model to test possible therapeutic modalities.

Glucocerebrosidase: Functions in and Beyond the Lysosome

“…For example, it was hypothesized that the accumulation of substrates of GCase is pathogenic; that GCase deficiency causes inhibition of autophagy and lysosomal degradative capacity and subsequently reduces turnover of αSyn; that increased αSyn levels impair the activity of GCase and vice versa; and, that GCase deficiency impairs mitochondria. Contrarily, it was proposed that mutant GCase protein may be toxic by inducing an excessive unfolded protein response in the ER or saturating the ubiquitin-proteasome pathway [129,130]. It is conceivable that multiple mechanisms may be involved in the GBA-PD pathology.…”

“…Inactivation of GCase with an irreversible inhibitor was found to increase gpNMB in the brain [143]. Interestingly, zebrafish and fruit flies overproduce a chitinase during GCase deficiency [130,145].…”

Are Glucosylceramide-Related Sphingolipids Involved in the Increased Risk for Cancer in Gaucher Disease Patients? Review and Hypotheses

“…For example, IL-4 synergizes with IL-6 and IL-10 to promote cathepsin secretion in tumor-associated macrophages via UPR activation, resulting in cancer cell invasion [107]. Moreover, in a GD fly model, in which (neuro)inflammation was initially observed, treatment with a GCase chaperone could reverse the phenotype, suggesting a role for GCase in inflammation [108]. Thus, the possibility that mutated GCase by itself could promote cancer by impairing protein degradation systems cannot be ruled out.…”

Heat shock proteins and small nucleolar RNAs are dysregulated in a Drosophila model for feline hypertrophic cardiomyopathy

“…Mutations in GBA have been associated with Gaucher disease (GD) type III in patients presenting with cardiovascular calcifications ( Beutler et al 1995 ; Chabas et al 1995 ; George et al 2001 ). Drosophila models for GD have been established to study the effects of mutant Gba1 ( Suzuki et al 2015 ; Davis et al 2016 ; Kinghorn et al 2016 ; Cabasso et al 2019 ). A Drosophila model for GD using two existing GBA1 mutant fly lines recapitulated hallmarks of GD including shortened lifespan, neuroinflammation, and activation of the unfolded protein response ( Cabasso et al 2019 ).…”

“…Drosophila models for GD have been established to study the effects of mutant Gba1 ( Suzuki et al 2015 ; Davis et al 2016 ; Kinghorn et al 2016 ; Cabasso et al 2019 ). A Drosophila model for GD using two existing GBA1 mutant fly lines recapitulated hallmarks of GD including shortened lifespan, neuroinflammation, and activation of the unfolded protein response ( Cabasso et al 2019 ).…”