Ambroxol effects in glucocerebrosidase and α‐synuclein transgenic mice

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.