Research ArticleParkinson’s Disease

A modulator of wild-type glucocerebrosidase improves pathogenic phenotypes in dopaminergic neuronal models of Parkinson’s disease

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Science Translational Medicine  16 Oct 2019:
Vol. 11, Issue 514, eaau6870
DOI: 10.1126/scitranslmed.aau6870

Boosting GCase activity in PD

Mutations in the GBA1 gene encoding the lysosomal enzyme β-glucocerebrosidase (GCase) represent the most common risk factor for Parkinson’s disease (PD). Because decreased wild-type GCase activity may be contributing to PD pathogenesis, activating the wild-type enzyme is a potential therapeutic approach. Burbulla et al. developed a new small-molecule modulator of wild-type GCase called S-181. This compound increased wild-type GCase activity and improved pathogenic phenotypes in iPSC-derived dopaminergic neurons generated from fibroblasts from patients with PD having both genetic and idiopathic forms of the disease as well as in GBA1 mutant mice. These findings point to activation of wild-type GCase as a potential therapeutic approach for various forms of PD that exhibit decreased GCase activity.

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