Expression of human Gaucher disease gene GBA generates neurodevelopmental defects and ER stress in Drosophila eye.
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.
National Institute of Advanced Industrial Science and Technology, Tsukuba, Ibaraki, Japan.
Takahiro
T
Suzuki
Masami
M
Shimoda
Kumpei
K
Ito
Shuji
S
Hanai
Hidenobu
H
Aizawa
Tomoki
T
Kato
Kazunori
K
Kawasaki
Terumi
T
Yamaguchi
Hyung Don
HD
Ryoo
Naoko
N
Goto-Inoue
Mitsutoshi
M
Setou
Shoji
S
Tsuji
Norio
N
Ishida
D000595:Amino Acid Sequence; D000818:Animals; D030801:Animals, Genetically Modified; D015153:Blotting, Western; D002478:Cells, Cultured; D002658:Developmental Disabilities / Q000235:genetics* / Q000473:pathology; D004195:Disease Models, Animal; D004331:Drosophila melanogaster / Q000235:genetics / Q000254:growth & development* / Q000378:metabolism; D059865:Endoplasmic Reticulum Stress; D005123:Eye / Q000196:embryology* / Q000254:growth & development / Q000378:metabolism; D005776:Gaucher Disease / Q000473:pathology*; D005962:Glucosylceramidase / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D009420:Nervous System / Q000378:metabolism / Q000473:pathology*; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction
D012333:RNA, Messenger; D005962:Glucosylceramidase