Ambroxol effects in glucocerebrosidase and α-synuclein transgenic mice.
Ann Neurol.. 2016-11-01; 80(5): 766-775
DOI: 10.1002/ana.24790
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1. Ann Neurol. 2016 Nov;80(5):766-775. doi: 10.1002/ana.24790.
Ambroxol effects in glucocerebrosidase and α-synuclein transgenic mice.
Migdalska-Richards A(1), Daly L(1), Bezard E(2)(3), Schapira AH(1).
Author information:
(1)Department of Clinical Neurosciences, Institute of Neurology, University
College London, London, United Kingdom.
(2)Neurodegenerative Diseases Institute, University of Bordeaux, Mixed Unit of
Research 5293, Bordeaux, France.
(3)Neurodegenerative Diseases Institute, National Center for Scientific Research,
Mixed Unit of Research 5293, Bordeaux, France.
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. Ann Neurol 2016;80:766-775.
© 2016 The Authors. Annals of Neurology published by Wiley Periodicals, Inc. on
behalf of American Neurological Association.
DOI: 10.1002/ana.24790
PMCID: PMC5132106
PMID: 27859541 [Indexed for MEDLINE]