Expression of human Gaucher disease gene GBA generates neurodevelopmental defects and ER stress in Drosophila eye

PLoS One. 2013 Aug 2;8(8):e69147. doi: 10.1371/journal.pone.0069147. Print 2013.

Abstract

Gaucher disease (GD) is the most common of the lysosomal storage disorders and is caused by defects in the GBA gene encoding glucocerebrosidase (GlcCerase). The accumulation of its substrate, glucocylceramide (GlcCer) is considered the main cause of GD. We found here that the expression of human mutated GlcCerase gene (hGBA) that is associated with neuronopathy in GD patients causes neurodevelopmental defects in Drosophila eyes. The data indicate that endoplasmic reticulum (ER) stress was elevated in Drosophila eye carrying mutated hGBAs by using of the ER stress markers dXBP1 and dBiP. We also found that Ambroxol, a potential pharmacological chaperone for mutated hGBAs, can alleviate the neuronopathic phenotype through reducing ER stress. We demonstrate a novel mechanism of neurodevelopmental defects mediated by ER stress through expression of mutants of human GBA gene in the eye of Drosophila.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Animals, Genetically Modified
  • Blotting, Western
  • Cells, Cultured
  • Developmental Disabilities / genetics*
  • Developmental Disabilities / pathology
  • Disease Models, Animal
  • Drosophila melanogaster / genetics
  • Drosophila melanogaster / growth & development*
  • Drosophila melanogaster / metabolism
  • Endoplasmic Reticulum Stress
  • Eye / embryology*
  • Eye / growth & development
  • Eye / metabolism
  • Gaucher Disease / pathology*
  • Glucosylceramidase / genetics*
  • Glucosylceramidase / metabolism
  • Humans
  • Molecular Sequence Data
  • Mutation / genetics*
  • Nervous System / metabolism
  • Nervous System / pathology*
  • RNA, Messenger / genetics
  • Real-Time Polymerase Chain Reaction
  • Reverse Transcriptase Polymerase Chain Reaction

Substances

  • RNA, Messenger
  • Glucosylceramidase

Grants and funding

This work was supported by an internal grant from National Institute of Advanced Industrial Science and Technology (http://www.aist.go.jp/) and by a grant from Nihon Advanced Agri Corporation (http://www.adv-agri.co.jp/). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.