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

Sanchez-Martinez, A; Beavan, M; Gegg, ME; Chau, K-Y; Whitworth, AJ; Schapira, AHV; (2016) Parkinson disease-linked GBA mutation effects reversed by molecular chaperones in human cell and fly models. Scientific Reports , 6 (31380) 10.1038/srep31380. Green open access

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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.

Type: Article
Title: Parkinson disease-linked GBA mutation effects reversed by molecular chaperones in human cell and fly models
Open access status: An open access version is available from UCL Discovery
DOI: 10.1038/srep31380
Publisher version: http://dx.doi.org/10.1038/srep31380
Language: English
Additional information: This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/
Keywords: Science & Technology, Multidisciplinary Sciences, Science & Technology - Other Topics, UNFOLDED PROTEIN RESPONSE, MIDBRAIN DOPAMINE NEURONS, GAUCHER-DISEASE, ALPHA-SYNUCLEIN, GLUCOCEREBROSIDASE MUTATIONS, MOUSE MODEL, ENDOPLASMIC-RETICULUM, LYSOSOMAL BIOGENESIS, DROSOPHILA MODEL, CA2+ STORES
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Clinical and Movement Neurosciences
URI: https://discovery.ucl.ac.uk/id/eprint/1508798
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