<i>Drosophila melanogaster</i> Mutated in its <i>GBA1b</i> Ortholog Recapitulates Neuronopathic Gaucher Disease
Gaucher disease (GD) results from mutations in the <i>GBA1</i> 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, t...
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doaj-5fd6fa9488374b24905aed87531c03292020-11-25T01:34:06ZengMDPI AGJournal of Clinical Medicine2077-03832019-09-0189142010.3390/jcm8091420jcm8091420<i>Drosophila melanogaster</i> Mutated in its <i>GBA1b</i> Ortholog Recapitulates Neuronopathic Gaucher DiseaseOr Cabasso0Sumit Paul1Orly Dorot2Gali Maor3Olga Krivoruk4Metsada Pasmanik-Chor5Mina Mirzaian6Maria Ferraz7Johannes Aerts8Mia Horowitz9School of Molecular Cell Biology and Biotechnology, Faculty of Life Sciences, Tel Aviv University, Ramat Aviv 69978, IsraelSchool of Molecular Cell Biology and Biotechnology, Faculty of Life Sciences, Tel Aviv University, Ramat Aviv 69978, IsraelSchool of Molecular Cell Biology and Biotechnology, Faculty of Life Sciences, Tel Aviv University, Ramat Aviv 69978, IsraelSchool of Molecular Cell Biology and Biotechnology, Faculty of Life Sciences, Tel Aviv University, Ramat Aviv 69978, IsraelSchool of Molecular Cell Biology and Biotechnology, Faculty of Life Sciences, Tel Aviv University, Ramat Aviv 69978, IsraelBioinformatics Unit, Faculty of life Science, Tel Aviv University, Ramat Aviv 69978, IsraelLeiden Institute of Chemistry, Leiden University, 9502 Leiden, The NetherlandsLeiden Institute of Chemistry, Leiden University, 9502 Leiden, The NetherlandsLeiden Institute of Chemistry, Leiden University, 9502 Leiden, The NetherlandsSchool of Molecular Cell Biology and Biotechnology, Faculty of Life Sciences, Tel Aviv University, Ramat Aviv 69978, IsraelGaucher disease (GD) results from mutations in the <i>GBA1</i> 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 <i>GBA1</i> orthologs, <i>GBA1a</i> and <i>GBA1b</i>. Each contains a Minos element insertion, which truncates its coding sequence. In the <i>GBA1a<sup>m/m</sup></i> flies, which express a mutant protein, missing 33 C-terminal amino acids, there was no decrease in GCase activity or substrate accumulation. However, <i>GBA1b<sup>m/m</sup></i> mutant flies presented a significant decrease in GCase activity with concomitant substrate accumulation, which included C14:1 glucosylceramide and C14:0 glucosylsphingosine. <i>GBA1b<sup>m/m</sup></i> 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 <i>GBA1b<sup>m/m</sup></i> mutant fly and neuronopathic GD and underlie its relevance in further GD studies as well as a model to test possible therapeutic modalities.https://www.mdpi.com/2077-0383/8/9/1420Gaucher diseaseglucocerebrosidaseGlcCerGlcSphinflammationunfolded protein response |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Or Cabasso Sumit Paul Orly Dorot Gali Maor Olga Krivoruk Metsada Pasmanik-Chor Mina Mirzaian Maria Ferraz Johannes Aerts Mia Horowitz |
spellingShingle |
Or Cabasso Sumit Paul Orly Dorot Gali Maor Olga Krivoruk Metsada Pasmanik-Chor Mina Mirzaian Maria Ferraz Johannes Aerts Mia Horowitz <i>Drosophila melanogaster</i> Mutated in its <i>GBA1b</i> Ortholog Recapitulates Neuronopathic Gaucher Disease Journal of Clinical Medicine Gaucher disease glucocerebrosidase GlcCer GlcSph inflammation unfolded protein response |
author_facet |
Or Cabasso Sumit Paul Orly Dorot Gali Maor Olga Krivoruk Metsada Pasmanik-Chor Mina Mirzaian Maria Ferraz Johannes Aerts Mia Horowitz |
author_sort |
Or Cabasso |
title |
<i>Drosophila melanogaster</i> Mutated in its <i>GBA1b</i> Ortholog Recapitulates Neuronopathic Gaucher Disease |
title_short |
<i>Drosophila melanogaster</i> Mutated in its <i>GBA1b</i> Ortholog Recapitulates Neuronopathic Gaucher Disease |
title_full |
<i>Drosophila melanogaster</i> Mutated in its <i>GBA1b</i> Ortholog Recapitulates Neuronopathic Gaucher Disease |
title_fullStr |
<i>Drosophila melanogaster</i> Mutated in its <i>GBA1b</i> Ortholog Recapitulates Neuronopathic Gaucher Disease |
title_full_unstemmed |
<i>Drosophila melanogaster</i> Mutated in its <i>GBA1b</i> Ortholog Recapitulates Neuronopathic Gaucher Disease |
title_sort |
<i>drosophila melanogaster</i> mutated in its <i>gba1b</i> ortholog recapitulates neuronopathic gaucher disease |
publisher |
MDPI AG |
series |
Journal of Clinical Medicine |
issn |
2077-0383 |
publishDate |
2019-09-01 |
description |
Gaucher disease (GD) results from mutations in the <i>GBA1</i> 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 <i>GBA1</i> orthologs, <i>GBA1a</i> and <i>GBA1b</i>. Each contains a Minos element insertion, which truncates its coding sequence. In the <i>GBA1a<sup>m/m</sup></i> flies, which express a mutant protein, missing 33 C-terminal amino acids, there was no decrease in GCase activity or substrate accumulation. However, <i>GBA1b<sup>m/m</sup></i> mutant flies presented a significant decrease in GCase activity with concomitant substrate accumulation, which included C14:1 glucosylceramide and C14:0 glucosylsphingosine. <i>GBA1b<sup>m/m</sup></i> 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 <i>GBA1b<sup>m/m</sup></i> mutant fly and neuronopathic GD and underlie its relevance in further GD studies as well as a model to test possible therapeutic modalities. |
topic |
Gaucher disease glucocerebrosidase GlcCer GlcSph inflammation unfolded protein response |
url |
https://www.mdpi.com/2077-0383/8/9/1420 |
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