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

TitleParkinson disease-linked GBA mutation effects reversed by molecular chaperones in human cell and fly models.
Publication TypeJournal Article
Year of Publication2016
AuthorsSanchez-Martinez, A, Beavan, M, Gegg, ME, Chau, K-Y, Whitworth, AJ, Schapira, AHV
JournalSci Rep
Date Published2016 Aug 19

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.

Alternate JournalSci Rep
Citation Key10.1038/srep31380
PubMed ID27539639
PubMed Central IDPMC4990939
Grant ListMC_UP_1501/1 / / Medical Research Council / United Kingdom
P40 OD018537 / OD / NIH HHS / United States
MR/M006646/1 / / Medical Research Council / United Kingdom
MR/L501499/1 / / Medical Research Council / United Kingdom
309742 / / European Research Council / International