| Title: |
A Drosophila Model of Neuronopathic Gaucher Disease Demonstrates Lysosomal-Autophagic Defects and Altered mTOR Signalling and Is Functionally Rescued by Rapamycin |
| Authors: |
Kinghorn, KJ; Groenke, S; Castillo-Quan, JI; Woodling, NS; Li, L; Sirka, E; Gegg, M; Mills, K; Hardy, J; Bjedov, I; Partridge, L |
| Source: |
JOURNAL OF NEUROSCIENCE , 36 (46) pp. 11654-11670. (2016) |
| Publisher Information: |
SOC NEUROSCIENCE |
| Publication Year: |
2016 |
| Collection: |
University College London: UCL Discovery |
| Subject Terms: |
Science & Technology; Life Sciences & Biomedicine; Neurosciences; Neurosciences & Neurology; autophagy; Drosophila; Gaucher disease; glucocerebrosidase; mTOR; rapamycin; TANDEM MASS-SPECTROMETRY; PARKINSONS-DISEASE; AMINO-ACIDS; MOUSE MODEL; V-ATPASE; LONGEVITY; MELANOGASTER; BIOGENESIS; PROTEINS; MICE |
| Description: |
Glucocerebrosidase (GBA1) mutations are associated with Gaucher disease (GD), an autosomal recessive disorder caused by functional deficiency of glucocerebrosidase (GBA), a lysosomal enzyme that hydrolyzes glucosylceramide to ceramide and glucose. Neuronopathic forms of GD can be associated with rapid neurological decline (Type II) or manifest as a chronic form (Type III) with a wide spectrum of neurological signs. Furthermore, there is now a well-established link between GBA1 mutations and Parkinson's disease (PD), with heterozygote mutations in GBA1 considered the commonest genetic defect in PD. Here we describe a novel Drosophila model of GD that lacks the two fly GBA1 orthologs. This knock-out model recapitulates the main features of GD at the cellular level with severe lysosomal defects and accumulation of glucosylceramide in the fly brain. We also demonstrate a block in autophagy flux in association with reduced lifespan, age-dependent locomotor deficits and accumulation of autophagy substrates in dGBA-deficient fly brains. Furthermore, mechanistic target of rapamycin (mTOR) signaling is downregulated in dGBA knock-out flies, with a concomitant upregulation of Mitf gene expression, the fly ortholog of mammalian TFEB, likely as a compensatory response to the autophagy block. Moreover, the mTOR inhibitor rapamycin is able to partially ameliorate the lifespan, locomotor, and oxidative stress phenotypes. Together, our results demonstrate that this dGBA1-deficient fly model is a useful platform for the further study of the role of lysosomal-autophagic impairment and the potential therapeutic benefits of rapamycin in neuronopathic GD. These results also have important implications for the role of autophagy and mTOR signaling in GBA1-associated PD. |
| Document Type: |
article in journal/newspaper |
| File Description: |
text |
| Language: |
English |
| Relation: |
https://discovery.ucl.ac.uk/id/eprint/1529772/1/11654.full.pdf; https://discovery.ucl.ac.uk/id/eprint/1529772/ |
| Availability: |
https://discovery.ucl.ac.uk/id/eprint/1529772/1/11654.full.pdf; https://discovery.ucl.ac.uk/id/eprint/1529772/ |
| Rights: |
open |
| Accession Number: |
edsbas.FF21B959 |
| Database: |
BASE |