TY - JOUR
T1 - A modulator of wild-type glucocerebrosidase improves pathogenic phenotypes in dopaminergic neuronal models of Parkinson’s disease
AU - Burbulla, Lena F.
AU - Jeon, Sohee
AU - Zheng, Jianbin
AU - Song, Pingping
AU - Silverman, Richard B.
AU - Krainc, Dimitri
N1 - Funding Information:
We thank K. Merchant and Y. C. Wong for helpful discussions. We thank the Northwestern Stem Cell Core Facility for the generation of iPSC lines from GBA1 mutation carriers. We thank K. Hunt for help with the protein binding assays. Lipid analyses were performed by the Lipidomics Shared Resource, Hollings Cancer Center, and Medical University of South Carolina. Pharmacokinetics were performed by the Northwestern Developmental Therapeutics Core and Integrated Molecular Structure Education and Research Center (IMSERC) at Northwestern University. We are grateful to N. Marotta for help with quantitative PCR. This work was supported by NIH grants no. R01NS076054 and R01NS096240 (to D.K.); WildKat LLC; Buckeye Research LLC (to D.K.); The Michael J. Fox Foundation for Parkinson?s Research (to J.Z.); and, in part, by NIH core support grant no. P30 NS081774
PY - 2019/10/16
Y1 - 2019/10/16
N2 - 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.
AB - 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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U2 - 10.1126/scitranslmed.aau6870
DO - 10.1126/scitranslmed.aau6870
M3 - Article
C2 - 31619543
AN - SCOPUS:85073455223
VL - 11
JO - Science Translational Medicine
JF - Science Translational Medicine
SN - 1946-6234
IS - 514
M1 - eaau6870
ER -