Abstract
Current treatments for Parkinson’s disease (PD) provide only symptomatic relief, with no disease-modifying therapies identified to date. Repurposing FDA-approved drugs to treat PD could significantly shorten the time needed for and reduce the costs of drug development compared with conventional approaches. We developed an efficient strategy to screen for modulators of β-glucocerebrosidase (GCase), a lysosomal enzyme that exhibits decreased activity in patients with PD, leading to accumulation of the substrate glucosylceramide and oxidized dopamine and α-synuclein, which contribute to PD pathogenesis. Using a GCase fluorescent probe and affinity-based fluorescence polarization assay, we screened 1280 structurally diverse, bioactive, and cell-permeable FDA-approved drugs and found that the antipsychotic quetiapine bound GCase with high affinity. Moreover, quetiapine treatment of induced pluripotent stem cell–derived (iPSC-derived) dopaminergic neurons from patients carrying mutations in GBA1 or LRRK2 led to increased wild-type GCase protein levels and activity and partially lowered accumulation of oxidized dopamine, glucosylceramide, and α-synuclein. Similarly, quetiapine led to activation of wild-type GCase and reduction of α-synuclein in a GBA mutant mouse model (Gba1D409V/+ mice). Together, these results suggest that repurposing quetiapine as a modulator of GCase may be beneficial for patients with PD exhibiting decreased GCase activity.
| Original language | English (US) |
|---|---|
| Article number | e148649 |
| Journal | JCI Insight |
| Volume | 6 |
| Issue number | 19 |
| DOIs | |
| State | Published - Oct 8 2021 |
Funding
We thank Northwestern High Throughput Analysis Laboratory for FP HTS and Northwestern Stem Cell Core Facility for iPSC line generation from the GBA1 mutation carriers. We thank Ai-zhi Bai for assistance with FP HTS and Nicolas Marotta and Sohee Jeon for mouse breeding and genotyping. Lipid analyses were performed by the Lipidomics Shared Resource, Hollings Cancer Center, and Medical University of South Carolina. Mouse drug administration was performed by the Northwestern Developmental Therapeutics Core at Northwestern University. This work was supported by NIH grants R01NS076054 and R01NS096240 (to DK); by The Michael J. Fox Foundation for Parkinson’s Research (13881 to JZ); by, in part, NIH core support grant P30 NS081774; and by the DFG (German Research Foundation) under Germany’s Excellence Strategy, within the framework of the Munich Cluster of Systems Neurology (EXC 2145 SyNergy — ID 390857198). We thank Northwestern High Throughput Analysis Laboratory for FP HTS and Northwestern Stem Cell Core Facility for iPSC line generation from the GBA1 mutation carriers. We thank Ai-zhi Bai for assistance with FP HTS and Nicolas Marotta and Sohee Jeon for mouse breeding and genotyping. Lipid analyses were performed by the Lipidomics Shared Resource, Hollings Cancer Center, and Medical University of South Carolina. Mouse drug administration was performed by the Northwestern Developmental Therapeutics Core at Northwestern University. This work was supported by NIH grants R01NS076054 and R01NS096240 (to DK); by The Michael J. Fox Foundation for Parkinson?s Research (13881 to JZ); by, in part, NIH core support grant P30 NS081774; and by the DFG (German Research Foundation) under Germany?s Excellence Strategy, within the framework of the Munich Cluster of Systems Neurology (EXC 2145 SyNergy ? ID 390857198).
ASJC Scopus subject areas
- General Medicine