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The marine-derived compound TAG alleviates Parkinson’s disease by restoring RUBCN-mediated lipid metabolism homeostasis

Abstract

Parkinson’s disease (PD) is the second most common neurodegenerative disease, and its prevalence is increasing. Currently, no effective therapies for PD exist. Marine-derived natural compounds are considered important resources for the discovery of new drugs due to their distinctive structures and diverse activities. In this study, tetrahydroauroglaucin (TAG), a polyketide isolated from a marine sponge, was found to have notable neuroprotective effects on MPTP/MPP+-induced neurotoxicity. RNA sequencing analysis and metabolomics revealed that TAG significantly improved lipid metabolism disorder in PD models. Further investigation indicated that TAG markedly decreased the accumulation of lipid droplets (LDs), downregulated the expression of RUBCN, and promoted autophagic flux. Moreover, conditional knockdown of Rubcn notably attenuated PD-like symptoms and the accumulation of LDs, accompanied by blockade of the neuroprotective effect of TAG. Collectively, our results first indicated that TAG, a promising PD therapeutic candidate, could suppress the accumulation of LDs through the RUBCN-autophagy pathway, which highlighted a novel and effective strategy for PD treatment.

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Fig. 1: TAG improved mitochondrial dysfunction and reduced apoptosis in MPP+-treated SH-SY5Y cells.
Fig. 2: Neuroprotective effects of TAG on MPP+-induced primary neurons.
Fig. 3: TAG protected against MPTP-induced pathology in vivo.
Fig. 4: TAG ameliorated MPP+/MPTP-induced lipid metabolic disorder in vivo and in vitro.
Fig. 5: TAG downregulated the expression of RUBCN.
Fig. 6: Knockdown of Rubcn abolished the protective effect of TAG against MPP+-induced toxicity.
Fig. 7: The effects of TAG on MPTP-induced PD model mice were abrogated after sh-Rubcn transfection.
Fig. 8: The inhibitory effect of TAG on the accumulation of LDs was mediated by the Rubcn-autophagy axis.

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Acknowledgements

This work was supported by grants from the National Natural Science Foundation of China (No. 81991523, 82003725) and the National Key R&D Programme of China (No. 2021ZD0202901). We thank Prof. RXT from Nanjing University for supplying the marine-derived natural compounds.

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GH and RXT conceived and designed the study. The natural compounds were provided by ZWT and RXT. PY, YL, QHH, XHX and SYM performed the experiments and analysed the data. PY and YL wrote the manuscript. JHD provided technical support. GH and ML revised the manuscript. All the authors have read and approved the final version of the manuscript.

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Correspondence to Ming Lu, Ren-xiang Tan or Gang Hu.

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Yang, P., Liu, Y., Tong, Zw. et al. The marine-derived compound TAG alleviates Parkinson’s disease by restoring RUBCN-mediated lipid metabolism homeostasis. Acta Pharmacol Sin 45, 1366–1380 (2024). https://doi.org/10.1038/s41401-024-01259-y

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