Drosophila melanogaster Mutated in its GBA1b Ortholog Recapitulates Neuronopathic Gaucher Disease

Or Cabasso; Sumit Paul; Orly Dorot; Gali Maor; Olga Krivoruk; Metsada Pasmanik-Chor; Mina Mirzaian; Maria Ferraz; Johannes Aerts; Mia Horowitz

doi:10.3390/jcm8091420

Drosophila melanogaster Mutated in its GBA1b Ortholog Recapitulates Neuronopathic Gaucher Disease

J Clin Med. 2019 Sep 9;8(9):1420. doi: 10.3390/jcm8091420.

Authors

Or Cabasso¹, Sumit Paul¹, Orly Dorot^{1

2}, Gali Maor^{1

3}, Olga Krivoruk¹, Metsada Pasmanik-Chor⁴, Mina Mirzaian⁵, Maria Ferraz⁵, Johannes Aerts⁵, Mia Horowitz⁶

Affiliations

¹ School of Molecular Cell Biology and Biotechnology, Faculty of Life Sciences, Tel Aviv University, Ramat Aviv 69978, Israel.
² Blavatnik Center for Drug Discovery, Tel Aviv University, Ramat Aviv 69978, Israel.
³ Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, 02115, USA.
⁴ Bioinformatics Unit, Faculty of life Science, Tel Aviv University, Ramat Aviv 69978, Israel.
⁵ Leiden Institute of Chemistry, Leiden University, 9502 Leiden, The Netherlands.
⁶ School of Molecular Cell Biology and Biotechnology, Faculty of Life Sciences, Tel Aviv University, Ramat Aviv 69978, Israel. horwitzm@tauex.tau.ac.il.

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 GBA1a^m/m flies, which express a mutant protein, missing 33 C-terminal amino acids, there was no decrease in GCase activity or substrate accumulation. However, GBA1b^m/m mutant flies presented a significant decrease in GCase activity with concomitant substrate accumulation, which included C14:1 glucosylceramide and C14:0 glucosylsphingosine. GBA1b^m/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 GBA1b^m/m mutant fly and neuronopathic GD and underlie its relevance in further GD studies as well as a model to test possible therapeutic modalities.

Keywords: Gaucher disease; GlcCer; GlcSph; glucocerebrosidase; inflammation; unfolded protein response.

Abstract

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