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Identification of salsolinol as an RNA m6A methylation inducer that mediates dopaminergic neuronal death by regulating YAP1 and autophagy

ABSTRACT: Identification of salsolinol as an RNA m6A methylation inducer that mediates dopaminergic neuronal death by regulating YAP1 and autophagy

PROVIDER: PRJNA1047040 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR27001145_1.fastq.gz	Fastqsanger.gz
	SRR27001145_2.fastq.gz	Fastqsanger.gz
	SRR27001146_1.fastq.gz	Fastqsanger.gz
	SRR27001146_2.fastq.gz	Fastqsanger.gz
	SRR27001147_1.fastq.gz	Fastqsanger.gz

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Identification of salsolinol as an RNA m6A methylation inducer that mediates dopaminergic neuronal death by regulating YAP1 and autophagy

Project description:Salsolinol (1-methyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline, Sal) is a catechol isoquinoline that can cause neurotoxicity because of its structural similarity with MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), an environmental toxin that causes Parkinson’s disease (PD). However, the mechanism by which Sal mediates dopaminergic neuronal death remains unclear. In this study, we found that Sal can significantly enhance the global level of N6-methyladenosine (m6A) mRNA methylation in PC12 cells, mainly by inducing the downregulation of the expression of m6A demethylase FTO (fat mass and obesity-associated protein) and ALKBH5 (alkB homolog 5). The results of the RNA-Seq analysis showed that Sal can exert a neurotoxic effect by regulating the Hippo signaling pathway through RNA methylation. We found that m6A reader YTHDF2 (YTH domain-containing family protein 2) promoted the degradation of m6A-containing YAP1 (Yes-associated protein 1) mRNA, which is a downstream key effector in the Hippo pathway. Additionally, the downregulation of YAP1 can also promote autophagy, indicating that the inter-regulation of YAP1 and autophagy can lead to neurotoxicity. Our findings showed the effect of Sal on m6A RNA methylation and revealed that Sal can act as an RNA modification inducer mediating dopaminergic neuronal death through YAP1 and autophagy. Our results provided greater insights into the neurotoxic effects of catechol isoquinolines and might be used as a reference for further assessing the involvement of RNA methylation in the pathogenesis of PD.

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

Project description:JOURNAL/nrgr/04.03/01300535-202503000-00032/figure1/v/2024-06-17T092413Z/r/image-tiff 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.

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