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.
Highlights
Drug repurposing has the potential to generate urgently needed disease-modifying treatment for Parkinson’s disease (PD), the second most common neurodegenerative disease [1], more quickly and in a more cost-effective manner compared with traditional de novo drug discovery
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
We developed an affinity-based fluorescence polarization (FP) high-throughput screen (HTS) to screen 1280 structurally diverse, bioactive, and cell-permeable compounds approved by the FDA
Summary
Drug repurposing has the potential to generate urgently needed disease-modifying treatment for Parkinson’s disease (PD), the second most common neurodegenerative disease [1], more quickly and in a more cost-effective manner compared with traditional de novo drug discovery. We and others have previously shown that decreased wild-type GCase activity might contribute to the pathogenesis in genetic and sporadic PD forms that are not linked to GBA1 mutations [6,7,8,9,10,11,12]. This suggests that activating the wild-type enzyme might be a viable therapeutic approach. We recently showed that modulation of wildtype GCase with a novel small molecule increased the enzyme activity and partially ameliorated pathological phenotypes in dopaminergic neurons from patients with GBA1-linked and non–GBA1-linked PD [13]
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