Glucocerebrosidase pharmacological chaperones attenuate α-synuclein-induced neurotoxicity in chronic cortico-striatal slices

Background: Parkinson's disease (PD) is characterized by the formation of proteinaceous aggregates of α-synuclein (α-syn) in cell bodies and neurites of Substantia Nigra pars compacta (SNpc) dopaminergic neurons, eventually causing cell death. Interestingly, defective activity or mutations in GBA1, the gene encoding the lysosomal enzyme Glucocerebrosidase (GCase), are the strongest risk factor to develop PD. Based on this evidence, reverting the cytological and molecular abnormalities caused by GCase mutations or enhancing the activity of the wild type enzyme may represent a feasible therapeutic strategy to oppose α-syn accumulation in PD.Aim: To evaluate the safety and pharmacokinetic profile of the GCase enhancer CF30 in vivo and assess its ability to: (1) enhance GCase activity, (2) prevent/oppose the accumulation α-syn aggregates in SHSY5Y cell lines and cortico-striatal organotypic slices.Methods: Chaperone-induced GCase enhancement and protective efficacy was assayed with biochemical and histological analyses on SHSY5Y cell lines and cortico-striatal organotypic slices treated with oligomers, fibrils, and monomers of α-syn.Results: CF30 is well tolerated at effective concentration/dosage in cell lines and in vivo and exhibits favourable pharmacokinetic profile with good oral availability and brain penetrance. GCase activity is enhanced by 40 and 18% in vitro and in vivo, respectively. On SHSY5Y cell lines and cortico-striatalorganotypic slices we have evaluated the protective action of GCase enhancement against the neurotoxic effects of oligomers and fibrils.