{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T18:00:11Z","timestamp":1790704811586,"version":"4.1.0"},"reference-count":53,"publisher":"Society for Neuroscience","issue":"46","license":[{"start":{"date-parts":[[2017,5,16]],"date-time":"2017-05-16T00:00:00Z","timestamp":1494892800000},"content-version":"vor","delay-in-days":181,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-sa\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["J. Neurosci."],"published-print":{"date-parts":[[2016,11,16]]},"abstract":"<jats:p>Glucocerebrosidase (<jats:italic>GBA1<\/jats:italic>) 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<jats:italic>GBA1<\/jats:italic>mutations and Parkinson's disease (PD), with heterozygote mutations in<jats:italic>GBA1<\/jats:italic>considered the commonest genetic defect in PD. Here we describe a novel<jats:italic>Drosophila<\/jats:italic>model of GD that lacks the two fly<jats:italic>GBA1<\/jats:italic>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<jats:italic>Mitf<\/jats:italic>gene expression, the fly ortholog of mammalian<jats:italic>TFEB<\/jats:italic>, 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<jats:italic>dGBA1<\/jats:italic>-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<jats:italic>PD<\/jats:italic>.<\/jats:p><jats:p><jats:bold>SIGNIFICANCE STATEMENT<\/jats:bold>We developed a<jats:italic>Drosophila<\/jats:italic>model of neuronopathic GD by knocking-out the fly orthologs of the<jats:italic>GBA1<\/jats:italic>gene, demonstrating abnormal lysosomal pathology in the fly brain. Functioning lysosomes are required for autophagosome-lysosomal fusion in the autophagy pathway. We show<jats:italic>in vivo<\/jats:italic>that autophagy is impaired in dGBA-deficient fly brains. In response, mechanistic target of rapamycin (mTOR) activity is downregulated in dGBA-deficient flies and rapamycin ameliorates the lifespan, locomotor, and oxidative stress phenotypes.<jats:italic>dGBA<\/jats:italic>knock-out flies also display an upregulation of the<jats:italic>Drosophila<\/jats:italic>ortholog of mammalian<jats:italic>TFEB<\/jats:italic>,<jats:italic>Mitf,<\/jats:italic>a response that is unable to overcome the autophagy block. Together, our results suggest that rapamycin may have potential benefits in the treatment of GD, as well as PD linked to<jats:italic>GBA1<\/jats:italic>mutations.<\/jats:p>","DOI":"10.1523\/jneurosci.4527-15.2016","type":"journal-article","created":{"date-parts":[[2016,11,16]],"date-time":"2016-11-16T21:25:21Z","timestamp":1479331521000},"page":"11654-11670","source":"Crossref","is-referenced-by-count":164,"title":["A<i>Drosophila<\/i>Model of Neuronopathic Gaucher Disease Demonstrates Lysosomal-Autophagic Defects and Altered mTOR Signalling and Is Functionally Rescued by Rapamycin"],"prefix":"10.1523","volume":"36","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2048-4332","authenticated-orcid":false,"given":"Kerri 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