Glucocerebrosidase activity, cathepsin D and monomeric α-synuclein interactions in a stem cell derived neuronal model of a PD associated GBA1 mutation

The presence of GBA1 gene mutations increases risk for Parkinson's disease (PD), but the pathogenic mechanisms of GBA1 associated PD remain unknown. Given that impaired alpha-synuclein turnover is a hallmark of PD pathogenesis and cathepsin D is a key enzyme involved in alpha-synuclein degradation in neuronal cells, we have examined the relationship of glucocerebrosidase (GCase), cathepsin D and monomeric alpha-synuclein in human neural crest stem cell derived dopaminergic neurons. We found that normal activity of GCase is necessary for cathepsin D to perform its function of monomeric alpha-synuclein removal from neurons. GBA1 mutations lead to a lower level of cathepsin D protein and activity, and higher level of monomeric alpha-synuclein in neurons. When GBA1 mutant neurons were treated with GCase replacement or chaperone therapy; cathepsin D protein levels and activity were restored, and monomeric alpha-synuclein decreased. When cathepsin D was inhibited, GCase replacement failed to reduce monomeric alpha-synuclein levels in GBA1 mutant neurons. These data indicate that GBA1 gene mutations increase monomeric alpha-synuclein levels via an effect on lysosomal cathepsin D in neurons.