The scientific justification for the repurposing of ambroxol for Parkinson’s

Introduction

Lysosomal dysfunction is implicated as playing a role in many cases of Parkinson’s disease (PD). Through associations with genetic risk factors and inherited diseases, as well as research in preclinical models, this cellular waste recycling process is now viewed as a potential avenue for corrective intervention. One common genetic risk locus associated with PD involves the glycosylceramidase beta (GBA1) gene, which encodes the lysosomal enzyme β-glucocerebrosidase (GCase). Carriers of GBA1 variants with PD typically display faster rates of progression and a higher risk of cognitive complaints, giving rise to a sub-type of PD known as “GBA-associated PD”. A reduction in levels of GCase activity is believed to bely this phenotype, leading to a search for agents that can elevate levels of this enzyme as potential therapeutics. Drug screening experiments have demonstrated that the clinically available secretolytic agent ambroxol binds to the active site of the GCase enzyme, stabilizing the protein, and transporting it to lysosomes. Numerous models of PD and recent clinical data indicate that ambroxol may have potentially beneficial properties in the context of PD. In this review, we will provide an overview of the current data supporting the justification for the repurposing of ambroxol as a possible disease modifying therapy for PD. We would welcome any thoughts from the wider research and Parkinson’s communities.