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

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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.

Abstract

Mutations in the GBA1 gene encoding the lysosomal enzyme β-glucocerebrosidase (GCase) represent the most common risk factor for Parkinson’s disease (PD). GCase has been identified as a potential therapeutic target for PD and current efforts are focused on chemical chaperones to translocate mutant GCase into lysosomes. However, for several GBA1-linked forms of PD and PD associated with mutations in LRRK2, DJ-1, and PARKIN, activating wild-type GCase represents an alternative approach. We developed a new small-molecule modulator of GCase called S-181 that increased wild-type GCase activity in iPSC-derived dopaminergic neurons from sporadic PD patients, as well as patients carrying the 84GG mutation in GBA1, or mutations in LRRK2, DJ-1, or PARKIN who had decreased GCase activity. S-181 treatment of these PD iPSC-derived dopaminergic neurons partially restored lysosomal function and lowered accumulation of oxidized dopamine, glucosylceramide and α-synuclein. Moreover, S-181 treatment of mice heterozygous for the D409V GBA1 mutation (Gba1D409V/+) resulted in activation of wild-type GCase and consequent reduction of GCase lipid substrates and α-synuclein in mouse brain tissue. Our findings point to activation of wild-type GCase by small-molecule modulators as a potential therapeutic approach for treating familial and sporadic forms of PD that exhibit decreased GCase activity.

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