Salsolinol as an RNA m~6A methylation inducer mediates dopaminergic neuronal death by regulating YAP1 and autophagy  

作　　者：Jianan Wang Yuanyuan Ran Zihan Li Tianyuan Zhao Fangfang Zhang Juan Wang Zongjian Liu Xuechai Chen 

机构地区：[1]Beijing International Science and Technology Cooperation Base for Antiviral Drugs,College of Chemistry and Life,Beijing University of Technology,Beijing,China [2]Department of Rehabilitation,Beijing Rehabilitation Hospital,Capital Medical University,Beijing,China

出　　处：《Neural Regeneration Research》2025年第3期887-899,共13页中国神经再生研究（英文版）

基　　金：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);the Scientific Research Project of Beijing Educational Committee,No.KM202010005022(to XC)。

摘　　要：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 N~6-methyladenosine(m~6A)RNA methylation in PC12 cells,mainly by inducing the downregulation of the expression of m~6A demethylases fat mass and obesity-associated protein(FTO)and alk B homolog 5(ALKBH5).RNA sequencing analysis showed that Sal downregulated the Hippo signaling pathway.The m~6A reader YTH domain-containing family protein 2(YTHDF2)promoted the degradation of m~6A-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 m~6A 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.

关 键 词：ALKBH5 AUTOPHAGY FTO Hippo pathway m~6A Parkinson's disease RNA methylation SALSOLINOL YAP1 YTHDF2 

分 类 号：R741[医药卫生—神经病学与精神病学]