Direct targeting of wild-type glucocerebrosidase by antipsychotic quetiapine improves pathogenic phenotypes in Parkinson’s disease models
| Autor: | Pingping Song, Lena F. Burbulla, Dimitri Krainc, Jianbin Zheng, Michaela E. Johnson, Weilan Jiang, Patrik Brundin |
|---|---|
| Rok vydání: | 2021 |
| Předmět: |
drug effects [Glucosylceramidase]
Parkinson's disease Drug Evaluation Preclinical pharmacology [Antipsychotic Agents] drug effects [Dopaminergic Neurons] Pharmacology genetics [Glucosylceramidase] Mice genetics [Parkinson Disease] metabolism [alpha-Synuclein] Drug screens drug effects [Induced Pluripotent Stem Cells] Chemistry metabolism [Dopaminergic Neurons] Dopaminergic Neurodegeneration Parkinson Disease General Medicine LRRK2 metabolism [Induced Pluripotent Stem Cells] Parkinson disease genetics [Parkinsonian Disorders] physiopathology [Parkinsonian Disorders] alpha-Synuclein Glucosylceramidase physiopathology [Parkinson Disease] drug effects [alpha-Synuclein] Research Article Antipsychotic Agents medicine.drug pharmacology [Quetiapine Fumarate] Induced Pluripotent Stem Cells metabolism [Parkinson Disease] metabolism [Parkinsonian Disorders] Glucosylceramides Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 Quetiapine Fumarate Parkinsonian Disorders Dopamine metabolism [Glucosylceramides] medicine Animals Humans ddc:610 Dopaminergic Neurons Drug Repositioning medicine.disease Symptomatic relief Quetiapine genetics [Leucine-Rich Repeat Serine-Threonine Protein Kinase-2] Glucocerebrosidase Neuroscience |
| Zdroj: | JCI insight 6(19), e148649 (2021). doi:10.1172/jci.insight.148649 JCI Insight |
| ISSN: | 2379-3708 |
| DOI: | 10.1172/jci.insight.148649 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|