Abstract
Aggregation of α-synuclein, a component of Lewy bodies (LBs) or Lewy neurites in Parkinson’s disease (PD), is strongly linked with disease development, making it an attractive therapeutic target. Inhibiting aggregation can slow or prevent the neurodegenerative process. However, the bottleneck towards achieving this goal is the lack of such inhibitors. In the current study, we established a high-throughput screening platform to identify candidate compounds for preventing the aggregation of α-synuclein among the natural products in our in-house compound library. We found that a small molecule, 03A10, i.e., (+)-desdimethylpinoresinol, which is present in the fruits of Vernicia fordii (Euphorbiaceae), modulated aggregated α-synuclein, but not monomeric α-synuclein, to prevent further elongation of α-synuclein fibrils. In α-synuclein-overexpressing cell lines, 03A10 (10 μM) efficiently prevented α-synuclein aggregation and markedly ameliorated the cellular toxicity of α-synuclein fibril seeds. In the MPTP/probenecid (MPTP/p) mouse model, oral administration of 03A10 (0.3 mg· kg−1 ·d−1, 1 mg ·kg−1 ·d−1, for 35 days) significantly alleviated behavioral deficits, tyrosine hydroxylase (TH) neuron degeneration and p-α-synuclein aggregation in the substantia nigra (SN). As the Braak hypothesis postulates that the prevailing site of early PD pathology is the gastrointestinal tract, we inoculated α-synuclein preformed fibrils (PFFs) into the mouse colon. We demonstrated that α-synuclein PFF inoculation promoted α-synuclein pathology and neuroinflammation in the gut and brain; oral administration of 03A10 (5 mg· kg−1 ·d−1, for 4 months) significantly attenuated olfactory deficits, α-synuclein accumulation and neuroinflammation in the olfactory bulb and SN. We conclude that 03A10 might be a promising drug candidate for the treatment of PD.
03A10 might be a novel drug candidate for PD treatment, as it inhibits α-synuclein aggregation by modulating aggregated α-synuclein rather than monomeric α-synuclein to prevent further elongation of α-synuclein fibrils and prevent α-synuclein toxicity in vitro, in an MPTP/p mouse model, and PFF-inoculated mice.
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Acknowledgements
The research reported in this publication was supported by grants from the National Science & Technology Major Project “Key New Drug Creation and Manufacturing Program”, China (2018ZX09711002-003-013), and the Scientific Innovation Project of the Chinese Academy of Sciences (XDA12040304 and XDA12040216). This project was supported by the Shanghai Committee of Science and Technology, China (18DZ2290200), and the Key-Area Research and Development Program of Guangdong Province (2020B0303070002).
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LYF conceived and designed the experiments; QW, ZXY, Yu Zhang, Ye Zhang, and LZ performed most experiments; SY and YY synthesized 03A10; CZ and NXZ performed NMR and ITC; JTL, ZJX, and WLZ performed the molecular docking experiment; and QW and LYF wrote the manuscript.
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Wang, Q., Yao, S., Yang, Zx. et al. Pharmacological characterization of the small molecule 03A10 as an inhibitor of α-synuclein aggregation for Parkinson’s disease treatment. Acta Pharmacol Sin 44, 1122–1134 (2023). https://doi.org/10.1038/s41401-022-01039-6
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DOI: https://doi.org/10.1038/s41401-022-01039-6
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