Expression of Human Gaucher Disease Gene GBA Generates Neurodevelopmental Defects and ER Stress in Drosophila Eye

Shuji Hanai,Norio Ishida,Takahiro Suzuki,Masami Shimoda,Kumpei Ito,Shoji Tsuji,Tomoki Kato,Hidenobu Aizawa,Naoko Goto-Inoue,Hyung Don Ryoo,Mitsutoshi Setou,Terumi Yamaguchi,Kazunori Kawasaki,Andrea Dardis

doi:10.1371/journal.pone.0069147

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.

Highlights

Individuals with Gaucher disease (GD) are deficient in the membrane-associated lysosomal enzyme, glucocerebrosidase (GlcCerase)
Western blotting showed a significant decrease in the total amount of hGBA protein in the hGBARecNciI transgenic combinations compared with the other transgenic combinations, because the RecNciI mutation includes L444P that is associated with protein degradation in patients with GD [30]
Neurodevelopmental defects in Drosophila eyes caused by hGBA with RecNciI mutation Here, we showed that hGBA with the RecNciI mutation, which caused type 2 GD, showed severe neurodevelopmental defects in Drosophila eyes

Summary

Introduction

Individuals with Gaucher disease (GD) are deficient in the membrane-associated lysosomal enzyme, glucocerebrosidase (GlcCerase). This reticuloendothelial storage disorder is clinically classified as types 1 (chronic, nonneuronopathic), 2 (acute, neuronopathic) and 3 (chronic, neuronopathic) [1]. The main treatment strategy is intravenous enzyme replacement, which might partly restore a deficient enzymatic capacity [10]. This strategy cannot prevent or treat neurological abnormalities, perhaps because GlcCerase cannot cross the blood–brain barrier [11] and no strategies are currently available to treat the neurological abnormalities associated with GD

Methods

Results

Conclusion