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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.

Parkinson disease-linked GBA mutation effects reversed by molecular chaperones in human cell and fly models