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Drosophila melanogaster Mutated in its GBA1b Ortholog Recapitulates Neuronopathic Gaucher Disease

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
*
Author to whom correspondence should be addressed.
J. Clin. Med. 2019, 8(9), 1420; https://doi.org/10.3390/jcm8091420
Received: 25 July 2019 / Revised: 4 September 2019 / Accepted: 5 September 2019 / Published: 9 September 2019
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. View Full-Text
Keywords: Gaucher disease; glucocerebrosidase; GlcCer; GlcSph; inflammation; unfolded protein response Gaucher disease; glucocerebrosidase; GlcCer; GlcSph; inflammation; unfolded protein response
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Cabasso, O.; Paul, S.; Dorot, O.; Maor, G.; Krivoruk, O.; Pasmanik-Chor, M.; Mirzaian, M.; Ferraz, M.; Aerts, J.; Horowitz, M. Drosophila melanogaster Mutated in its GBA1b Ortholog Recapitulates Neuronopathic Gaucher Disease. J. Clin. Med. 2019, 8, 1420.

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