Neural Regeneration Research ›› 2025, Vol. 20 ›› Issue (3): 887-899.doi: 10.4103/NRR.NRR-D-23-01592

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Salsolinol as an RNA m6A methylation inducer mediates dopaminergic neuronal death by regulating YAP1 and autophagy

Jianan Wang1, #, Yuanyuan Ran2, #, Zihan Li1, Tianyuan Zhao1, Fangfang Zhang1, Juan Wang1, *, Zongjian Liu2, *, Xuechai Chen1, *   

  1. 1Beijing International Science and Technology Cooperation Base for Antiviral Drugs, College of Chemistry and Life, Beijing University of Technology, Beijing, China; 2Department of Rehabilitation, Beijing Rehabilitation Hospital, Capital Medical University, Beijing, China
  • Online:2025-03-15 Published:2024-06-26
  • Contact: Juan Wang, PhD, juanwang@bjut.edu.cn; Zongjian Liu, PhD, liuzj888@ccmu.edu.cn; Xuechai Chen, PhD, chenxuechai@bjut.edu.cn.
  • Supported by:
    This study was supported by the National Natural Science Foundation of China, Nos. 82271283 (to XC), 91854115 (to JW), 31970044 (to JW); the Natural Science Foundation of Beijing, No. 7202001 (to XC); and the Scientific Research Project of Beijing Educational Committee, No. KM202010005022 (to XC).

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Abstract: Salsolinol (1-methyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline, Sal) is a catechol isoquinoline that causes neurotoxicity and shares structural similarity with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, an environmental toxin that causes Parkinson’s disease. However, the mechanism by which Sal mediates dopaminergic neuronal death remains unclear. In this study, we found that Sal significantly enhanced the global level of N6-methyladenosine (m6A) RNA methylation in PC12 cells, mainly by inducing the downregulation of the expression of m6A demethylases fat mass and obesity-associated protein (FTO) and alkB homolog 5 (ALKBH5). RNA sequencing analysis showed that Sal downregulated the Hippo signaling pathway. The m6A reader YTH domain-containing family protein 2 (YTHDF2) promoted the degradation of m6A-containing Yes-associated protein 1 (YAP1) mRNA, which is a downstream key effector in the Hippo signaling pathway. Additionally, downregulation of YAP1 promoted autophagy, indicating that the mutual regulation between YAP1 and autophagy can lead to neurotoxicity. These findings reveal the role of Sal on m6A RNA methylation and suggest that Sal may act as an RNA methylation inducer mediating dopaminergic neuronal death through YAP1 and autophagy. Our results provide greater insights into the neurotoxic effects of catechol isoquinolines compared with other studies and may be a reference for assessing the involvement of RNA methylation in the pathogenesis of Parkinson’s disease.

Key words: ALKBH5, autophagy, FTO, Hippo pathway, m6A, Parkinson’s disease, RNA methylation, salsolinol, YAP1, YTHDF2