Migdalska-Richards, A;
Daly, L;
Bezard, E;
Schapira, AHV;
(2016)
Ambroxol effects in glucocerebrosidase and -synuclein transgenic mice.
Annals of Neurology
, 80
(5)
pp. 766-775.
10.1002/ana.24790.
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Abstract
Objective. Gaucher disease is caused by mutations in the glucocerebrosidase 1 gene that result in deficiency of the lysosomal enzyme glucocerebrosidase. Both homozygous and heterozygous glucocerebrosidase 1 mutations confer an increased risk for developing Parkinson disease. Current estimates indicate that 10 to 25% of Parkinson patients carry glucocerebrosidase 1 mutations. Ambroxol is a small molecule chaperone that has been shown to increase glucocerebrosidase activity in vitro. This study investigated the effect of ambroxol treatment on glucocerebrosidase activity and on α-synuclein and phosphorylated α-synuclein protein levels in mice. Methods. Mice were treated with ambroxol for 12 days. After the treatment, glucocerebrosidase activity was measured in the mouse brain lysates. The brain lysates were also analyzed for α-synuclein and phosphorylated α-synuclein protein levels. Results. Ambroxol treatment resulted in increased brain glucocerebrosidase activity in (1) wild-type mice, (2) transgenic mice expressing the heterozygous L444P mutation in the murine glucocerebrosidase 1 gene, and (3) transgenic mice overexpressing human α-synuclein. Furthermore, in the mice overexpressing human α-synuclein, ambroxol treatment decreased both α-synuclein and phosphorylated α-synuclein protein levels. Interpretation. Our work supports the proposition that ambroxol should be further investigated as a potential novel disease-modifying therapy for treatment of Parkinson disease and neuronopathic Gaucher disease to increase glucocerebrosidase activity and decrease α-synuclein and phosphorylated α-synuclein protein levels.
Type: | Article |
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Title: | Ambroxol effects in glucocerebrosidase and -synuclein transgenic mice |
Open access status: | An open access version is available from UCL Discovery |
DOI: | 10.1002/ana.24790 |
Publisher version: | http://dx.doi.org/10.1002/ana.24790 |
Additional information: | © 2016 The Authors. Annals of Neurology published by Wiley Periodicals, Inc. on behalf of American Neurological Association. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. |
Keywords: | Science & Technology, Life Sciences & Biomedicine, Clinical Neurology, Neurosciences, Neurosciences & Neurology, ACID BETA-GLUCOSIDASE, GAUCHER-DISEASE, PARKINSON DISEASE, ALPHA-SYNUCLEIN, THERAPEUTIC STRATEGY, CARRIERS, PHOSPHORYLATION, IDENTIFICATION, DYSFUNCTION, CHAPERONES |
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/1530599 |
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