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Neural Regen Res. 2017 Mar;12(3):380-384. doi: 10.4103/1673-5374.202934.

The emerging role of autophagic-lysosomal dysfunction in Gaucher disease and Parkinson's disease.

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Institute of Healthy Ageing and Department of Genetics, Evolution and Environment, University College London, London, UK.
Institute of Neurology, University College London, London, UK.
Department of Basic and Clinical Neuroscience, King's College London, Maurice Wohl Clinical Neuroscience Institute, London, UK.
London Central & West Unscheduled Care Collaborative, St. Charles Centre for Health and Wellbeing, Exmoor Street St, Charles Hospital, London, UK.
Research Division, Joslin Diabetes Center, Boston, MA, USA.
Department of Genetics and Harvard Stem Cell Institute, Harvard Medical School, Boston, MA, USA.


Gaucher disease (GD), the commonest lysosomal storage disorder, results from the lack or functional deficiency of glucocerebrosidase (GCase) secondary to mutations in the GBA1 gene. There is an established association between GBA1 mutations and Parkinson's disease (PD), and indeed GBA1 mutations are now considered to be the greatest genetic risk factor for PD. Impaired lysosomal-autophagic degradation of cellular proteins, including α-synuclein (α-syn), is implicated in the pathogenesis of PD, and there is increasing evidence for this also in GD and GBA1-PD. Indeed we have recently shown in a Drosophila model lacking neuronal GCase, that there are clear lysosomal-autophagic defects in association with synaptic loss and neurodegeneration. In addition, we demonstrated alterations in mechanistic target of rapamycin complex 1 (mTORC1) signaling and functional rescue of the lifespan, locomotor defects and hypersensitivity to oxidative stress on treatment of GCase-deficient flies with the mTOR inhibitor rapamycin. Moreover, a number of other recent studies have shown autophagy-lysosomal system (ALS) dysfunction, with specific defects in both chaperone-mediated autophagy (CMA), as well as macroautophagy, in GD and GBA1-PD model systems. Lastly we discuss the possible therapeutic benefits of inhibiting mTOR using drugs such as rapamycin to reverse the autophagy defects in GD and PD.


Drosophila; GBA; Gaucher disease; Parkinson's disease; autophagy; glucocerebrosidase; lysosome

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