Effects of ambroxol treatment on lipidomic and metabolomic profiles in brain and plasma in Pink1-/-SNCA A53T double mutant Parkinson's Disease mice

ABSTRACT: The pathology of Parkinson's Disease (PD) arises from a deposition of oligomeric forms of alpha-synuclein (gene: SNCA, alphaSyn). Glycosphingolipids facilitate the formation of such oligomers and interfere with their lysosomal degradation. Consequently, mutations in genes involved in glycosphingolipid transport and degradation enhance the risk and severity of PD, and ambroxol which is an oral mucolytic drug was found to improve the folding of mutated or dysfunctional GBA1 and thereby its enzymatic activity. It is therefore proposed as add-on treatment for PD, and presently tested in clinical trials. Here, we studied the therapeutic efficacy of ambroxol in a mouse model of PD characterized by knockout of PTEN induced kinase (PINK1) plus transgene expression of human mutant SNCA A53T. Starting in the premotor phase, Pink1SNCA double mutant mice were treated with high doses of ambroxol via food pellets (approximately 75-100 mg/kg/d) for ca. 6 months. Control groups received placebo. Mice were observed in behavioural experiments and final tissue samples were subjected lipidomic and metabolomic analyses. Ambroxol was well tolerated and showed a mild improvement of slowness of PD mice at the behavioral level. Lipidomic profiles strongly differed between wildtype and Pink1SNCA mice irrespective on ambroxol treatment. Direct comparison of ambroxol versus placebo treated PD mice showed higher sulfatides in the brain in the ambroxol group, but most brain lipid species and brain polar metabolites did not differ between the treatments groups. In plasma, levels of cholesteryl esters (CE) were higher in the ambroxol groups compared by placebo treated mice. Ambroxol treatment restored the levels of some polar metabolites in plasma to levels of wildtype mice, including metabolites of dopamine and serotonin. Methods are described in S-BSST1888 and S-BSST389.

ORGANISM(S): Mus musculus (mouse)

SUBMITTER:  

PROVIDER: S-BSST1946 | biostudies-other |

SECONDARY ACCESSION(S): S-BSST1888

REPOSITORIES: biostudies-other