Format

Send to

Choose Destination
Ann Neurol. 2016 Nov;80(5):766-775. doi: 10.1002/ana.24790.

Ambroxol effects in glucocerebrosidase and α-synuclein transgenic mice.

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.

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. Ann Neurol 2016;80:766-775.

PMID:
27859541
PMCID:
PMC5132106
DOI:
10.1002/ana.24790
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Wiley Icon for PubMed Central
Loading ...
Support Center