Anti-apoptotic capacity of MALAT1 on hippocampal neurons correlates with CASP3 DNA methylation in a mouse model of autism.

Abstract

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.