RESUMO
Prior evidence has suggested the alleviatory effect of metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) on neuroinflammation in neurodegenerative diseases. This study primarily investigates the underlying mechanism of how the long non-coding RNA MALAT1 affects neuronal apoptosis in the hippocampus of mice with autism spectrum disorder (ASD). The findings demonstrate that CASP3 is highly expressed while MALAT1 is downregulated in the hippocampal neurons of autistic mice. MALAT1 mainly localizes within the cell nucleus and recruits DNA methyltransferases (including DNMT1, DNMT3a, and DNMT3b) to the promoter region of CASP3, promoting its methylation and further inhibiting its expression. In vitro experiments reveal that reducing MALAT1 expression promotes the expression of CASP3 and Bax while suppressing Bcl-2 expression, thereby enhancing cellular apoptosis. Conversely, increasing MALAT1 expression yields the opposite effect. Consequently, these results further confirm the role of MALAT1 in suppressing neuronal apoptosis in the hippocampus of mice with ASD through the regulation of CASP3 promoter methylation. Thus, this research unveils the significant roles of MALAT1 and CASP3 in the pathogenesis of ASD, offering new possibilities for future therapeutic interventions.
Assuntos
Transtorno do Espectro Autista , Transtorno Autístico , Caspase 3 , RNA Longo não Codificante , Animais , Camundongos , Apoptose/genética , Transtorno do Espectro Autista/genética , Transtorno do Espectro Autista/metabolismo , Transtorno Autístico/genética , Transtorno Autístico/metabolismo , Caspase 3/metabolismo , Proliferação de Células , Modelos Animais de Doenças , Metilação de DNA , Hipocampo/metabolismo , Neurônios/metabolismo , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismoRESUMO
OBJECTIVE: Hippocampal neuron apoptosis contributes to autism, while METTL3 has been documented to possess great potentials in neuron apoptosis. Our study probed into the role of METTL3 in neuron apoptosis in autism and to determine the underlying mechanism. METHODS: Bioinformatics analysis was used to analyze expressed genes in autism samples. Institute of Cancer Research mice were treated with valproic acid to develop autism models. The function of METTL3 in autism-like symptoms in mice was analyzed with behavioral tests and histological examination of their hippocampal tissues. Primary mouse hippocampal neurons were extracted for in vitro studies. Downstream factors of METTL3 were explored and validated. RESULTS: METTL3, MALAT1, and Wnt/ß-catenin signaling were downregulated, while SFRP2 was upregulated in the hippocampal tissues of a mouse model of autism. METTL3 stabilized MALAT1 expression by promoting m6A modification of MALAT1. MALAT1 promoted SFRP2 methylation and led to reduced SFRP2 expression by recruiting DNMT1, DNMT3A, and DNMT3B to the promoter region of SFRP2. Furthermore, SFRP2 facilitated activation of the Wnt/ß-catenin signaling. By this mechanism, METTL3 suppressed autism-like symptoms and hippocampal neuron apoptosis. CONCLUSION: This research suggests that METTL3 can reduce autism-like symptoms and hippocampal neuron apoptosis by regulating the MALAT1/SFRP2/Wnt/ß-catenin axis.
