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The Notch1/Hes1 signaling pathway affects autophagy by adjusting DNA methyltransferases expression in a valproic acid-induced autism spectrum disorder model.
- Source :
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Neuropharmacology [Neuropharmacology] 2023 Nov 15; Vol. 239, pp. 109682. Date of Electronic Publication: 2023 Aug 04. - Publication Year :
- 2023
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Abstract
- As a pervasive neurodevelopmental disease, autism spectrum disorder (ASD) is caused by both hereditary and environmental elements. Research has demonstrated the functions of the Notch pathway and DNA methylation in the etiology of ASD. DNA methyltransferases DNMT3 and DNMT1 are responsible for methylation establishment and maintenance, respectively. In this study, we aimed to explore the association of DNA methyltransferases with the Notch pathway in ASD. Our results showed Notch1 and Hes1 were upregulated, while DNMT3A and DNMT3B were downregulated at the protein level in the prefrontal cortex (PFC), hippocampus (HC) and cerebellum (CB) of VPA-induced ASD rats compared with Control (Con) group. However, the protein levels of DNMT3A and DNMT3B were augmented after treatment with 3,5-difluorophenacetyl-L-alanyl-S-phenylglycine-2-butyl ester (DAPT), suggesting that abnormal Notch pathway activation may affect the expression of DNMT3A and DNMT3B. Besides, our previous findings revealed that the Notch pathway may participate in development of ASD by influencing autophagy. Therefore, we hypothesized the Notch pathway adjusts autophagy and contributes to ASD by affecting DNA methyltransferases. Our current results showed that after receiving the DNA methyltransferase inhibitor 5-Aza-2'-deoxycytidine (5-Aza-2'dc), the VPA + DAPT+5-Aza-2'dc (V + D + Aza) group exhibited reduced social interaction ability and increased stereotyped behaviors, and decreased expression of DNMT3A, DNMT3B and autophagy-related proteins, but did not show changes in Notch1 and Hes1 protein levels. Our results indicated that the Notch1/Hes1 pathway may adjust DNMT3A and DNMT3B expression and subsequently affect autophagy in the occurrence of ASD, providing new insight into the pathogenesis of ASD.<br />Competing Interests: Declaration of competing interest The authors declared no potential competing financial interests or personal relationship that could have appeared to influence the work reported in this paper.<br /> (Copyright © 2023 Elsevier Ltd. All rights reserved.)
- Subjects :
- Rats
Animals
DNA Methylation
Signal Transduction
DNA Modification Methylases metabolism
DNA metabolism
Autophagy
Transcription Factor HES-1 genetics
Transcription Factor HES-1 metabolism
Receptor, Notch1 genetics
Receptor, Notch1 metabolism
Valproic Acid pharmacology
Autism Spectrum Disorder chemically induced
Autism Spectrum Disorder genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1873-7064
- Volume :
- 239
- Database :
- MEDLINE
- Journal :
- Neuropharmacology
- Publication Type :
- Academic Journal
- Accession number :
- 37543138
- Full Text :
- https://doi.org/10.1016/j.neuropharm.2023.109682