Ambroxol displaces α-synuclein from the membrane and inhibits the formation of early protein–lipid coaggregates

Parkinson's disease (PD) is a neurological disorder characterized by neuronal loss and the deposition of α-synuclein-lipid coaggregates in the brain of patients as well as disruptions in lipid metabolism. Mutations in the gene <i>GBA</i>, which encodes the lysosomal glycoprotein Glucocerebrosidase, are together the most important genetic risk factor for PD and have been associated with lysosomal dysfunction, accumulation of pathological α-synuclein as well as major changes in both the levels and properties of lipids. Ambroxol, a small molecule chaperone capable of binding and stabilizing Glucocerebrosidase, was found to revert changes in lipid levels and increase in α-synuclein levels due to <i>GBA</i> mutations potentially <i>via</i> restoring lysosomal function. Here, we show that Ambroxol also has a direct effect on α-synuclein-lipid coaggregation by inhibiting the primary nucleation step in the aggregation process. We find that Ambroxol not only displaces α-synuclein from negatively charged membranes but also prevents the formation of early α-synuclein-lipid coaggregates during primary nucleation. These results suggest that Ambroxol may have beneficial effects on other synucleinopathies, such as multiple system atrophy and dementia with Lewy Bodies, that are also characterised by the aggregation of α-synuclein into amyloid fibrils.