Abstract
GBA gene mutations are the greatest cause of Parkinson disease (PD). GBA encodes the lysosomal enzyme glucocerebrosidase (GCase) but the mechanisms by which loss of GCase contributes to PD remain unclear. Inhibition of autophagy and the generation of endoplasmic reticulum (ER) stress are both implicated. Mutant GCase can unfold in the ER and be degraded via the unfolded protein response, activating ER stress and reducing lysosomal GCase. Small molecule chaperones that cross the blood brain barrier help mutant GCase refold and traffic correctly to lysosomes are putative treatments for PD. We treated fibroblast cells from PD patients with heterozygous GBA mutations and Drosophila expressing human wild-type, N370S and L444P GBA with the molecular chaperones ambroxol and isofagomine. Both chaperones increased GCase levels and activity, but also GBA mRNA, in control and mutant GBA fibroblasts. Expression of mutated GBA in Drosophila resulted in dopaminergic neuronal loss, a progressive locomotor defect, abnormal aggregates in the ER and increased levels of the ER stress reporter Xbp1-EGFP. Treatment with both chaperones lowered ER stress and prevented the loss of motor function, providing proof of principle that small molecule chaperones can reverse mutant GBA-mediated ER stress in vivo and might prove effective for treating PD.
Highlights
The GBA gene encodes the lysosomal enzyme glucocerebrosidase (GCase), which cleaves the sphingolipid glucosylceramide into glucose and ceramide
We chose fibroblasts to investigate small molecule chaperones on mutant GBA, to be confident that any effects observed on endoplasmic reticulum (ER) stress were not due to the contribution of the well characterised relationship between perturbed α-synuclein homeostasis and mutant GCase reported in neurons and brain[14,15,16]
GCase activity was measured in control fibroblasts, fibroblasts from Parkinson disease (PD) patients with heterozygous GBA mutations (N370S/wt and L444P/wt) and fibroblasts from idiopathic PD patients
Summary
The GBA gene encodes the lysosomal enzyme glucocerebrosidase (GCase), which cleaves the sphingolipid glucosylceramide into glucose and ceramide. Occasional reports of GD with PD appeared some years ago[2,3], the link between GBA mutations and PD was clearly established in 20094. Both homozygous and heterozygous GBA mutations are associated with an approximately equal risk for the development of PD. In cellular and animal models where GCase is knocked down, knocked out or which express pathogenic mutations, α-synuclein is found to accumulate, exhibit properties of Lewy bodies (proteinase K resistant; ubiquitin positive) and be co-incident with impairment of the ALP14–17. Homozygous GBA mutations but no evidence of glucosylceramide accumulation in PD brains with heterozygous GBA mutations has been reported[20]
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