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  1. Kerri Kinghorn1,2,
  2. Sebastian Gronke3,
  3. Jorge Ivan Castillo-Quan1,2,
  4. Li Li2,
  5. Nathaniel Woodling2,
  6. Ernestas Sirka4,
  7. Matt Gegg1,
  8. John Hardy1,
  9. Linda Partridge2
  1. 1Institute of Neurology, UCL
  2. 2Institute of Healthy Ageing, UCL
  3. 3Max Planck Institute for Biology of Ageing, Köln, Germany
  4. 4Centre for Translational Omics, Institute of Child Health, UCL


Glucocerebrosidase (GBA1) mutations are associated with Gaucher disease (GD), the commonest lysosomal storage disorder, and are considered the commonest genetic defect in Parkinson's disease (PD). GBA1 encodes a lysosomal enzyme, glucocerebrosidase (GBA), which hydrolyses glucosylceramide to ceramide and glucose. Neuronopathic GD can be associated with rapid neurological decline and death in infancy (Type II) or manifests as a chronic form (Type III) with a wide spectrum of neurological signs. Here we describe a novel Drosophila model of GBA1 loss-of-function that recapitulates the main features of GD at the cellular level with severe lysosomal defects and accumulation of the GBA substrate glucosylceramide in the fly brain. We also report the in vivo demonstration of autophagy block in the brains of GBA-deficient flies. This autophagy impairment occurs in association with reduced lifespan and age-dependent locomotor deficits and p62 and ubiquitinated protein aggregates in the fly brain. Finally, the mTOR inhibitor rapamycin is able to partially ameliorate the lifespan, starvation and oxidative stress phenotypes. Taken together our results suggest that this GBA1 knockout fly model is a useful platform for the further study of the role of lysosomal-autophagic impairment and the possible potential therapeutic benefits of rapamycin in neuronopathic GD and GBA1-associated PD.

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