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

Pei Yang1, Yang Liu1, Zhi-wu Tong2, Qian-hui Huang1, Xia-hong Xie1, Shi-yu Mao3, Jian-hua Ding3, Ming Lu3, Ren-xiang Tan2, Gang Hu1,3
1 Department of Pharmacology, Nanjing University of Chinese Medicine, Nanjing 210023, China
2 State Key Laboratory of Pharmaceutical Biotechnology, Institute of Functional Biomolecules, School of Life Sciences, Nanjing University, Nanjing 210023, China
3 Jiangsu Key Laboratory of Neurodegeneration, Department of Pharmacology, Nanjing Medical University, Nanjing 211116, China
Correspondence to: Ming Lu:, Ren-xiang Tan:, Gang Hu:,
DOI: 10.1038/s41401-024-01259-y
Received: 12 September 2023
Accepted: 29 February 2024
Advance online: 27 March 2024


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.
Keywords: Parkinson’s disease; compound TAG; lipid metabolism; RUBCN

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