| First Author | Migdalska-Richards A | Year | 2016 |
| Journal | Ann Neurol | Volume | 80 |
| Issue | 5 | Pages | 766-775 |
| PubMed ID | 27859541 | Mgi Jnum | J:350195 |
| Mgi Id | MGI:7661161 | Doi | 10.1002/ana.24790 |
| Citation | Migdalska-Richards A, et al. (2016) Ambroxol effects in glucocerebrosidase and alpha-synuclein transgenic mice. Ann Neurol 80(5):766-775 |
| abstractText | 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 alpha-synuclein and phosphorylated alpha-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 alpha-synuclein and phosphorylated alpha-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 alpha-synuclein. Furthermore, in the mice overexpressing human alpha-synuclein, ambroxol treatment decreased both alpha-synuclein and phosphorylated alpha-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 alpha-synuclein and phosphorylated alpha-synuclein protein levels. Ann Neurol 2016;80:766-775. |
