JUN and PDGFRA as Crucial Candidate Genes for Childhood Autism Spectrum Disorder

Li, Heli; Wang, Xinyuan; Hu, Cong; Li, Hao; Xu, Zhuoshuo; Lei, Ping; Luo, Xiaoping; Yan, Hao

doi:10.3389/fninf.2022.800079

Cited by 12 publications

(12 citation statements)

References 77 publications

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“…As depicted in Fig. 6 A and B, glycogen synthase kinase 3 β (Gsk3b) emerged as the top-ranked gene in both networks based on the Degree of centrality and betweenness (Li et al 2022 ). It has been well-established that activated AKT can interact with numerous downstream proteins, and GSK-3β has been confirmed to play a role in neuronal apoptosis signaling (Razani et al 2021 ).…”

Section: Resultsmentioning

confidence: 99%

“…Timed pregnancies were established by pairing a male and female overnight, and the mid-day of the next morning was designated as embryonic day 0.5 (E0.5). Maternal immune activation (MIA) was performed according to a previously described method (Li et al 2022 ). Briefly, mice were mated overnight, and the presence of seminal plugs was checked every morning, which was recorded as embryonic Day 0.5 (E0.5).…”

Section: Methodsmentioning

confidence: 99%

“…The enrichment network of differentially expressed genes (DEGs) and Over-Representation Analysis (ORA)-generated heatmaps were performed using Network Analyst (Zhou et al 2019 ), a website that can generate tissue-specific Protein-Protein Interaction Networks (PPI) and gene co-expression networks. The network-based bioinformatics analysis utilized the Fisher’s method with a significance level of p < 0.05, as implemented in NetworkAnalyst, following the pipeline described by Li et al ( 2022 ).…”

Section: Methodsmentioning

confidence: 99%

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IL-6 Enhances the Activation of PI3K-AKT/mTOR-GSK-3β by Upregulating GRPR in Hippocampal Neurons of Autistic Mice

Li,

Wang,

et al. 2024

J Neuroimmune Pharmacol

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Autism spectrum disorder (ASD) is a neurological disorder associated with brain inflammation. The underlying mechanisms could be attributed to the activation of PI3K signaling in the inflamed brain of ASD. Multiple studies highlight the role of GRPR in regulating ASD like abnormal behavior and enhancing the PI3K signaling. However, the molecular mechanism by which GRPR regulates PI3K signaling in neurons of individuals with ASD is still unclear. In this study, we utilized a maternal immune activation model to investigate the effects of GRPR on PI3K signaling in the inflamed brain of ASD mice. We used HT22 cells with and without GRPR to examine the impact of GRP-GRPR on the PI3K-AKT pathway with IL-6 treatment. We analyzed a dataset of hippocampus samples from ASD mice to identify hub genes. Our results demonstrated increased expression of IL-6, GRPR, and PI3K-AKT signaling in the hippocampus of ASD mice. Additionally, we observed increased GRPR expression and PI3K-AKT/mTOR activation in HT22 cells after IL-6 treatment, but decreased expression in HT22 cells with GRPR knockdown. NetworkAnalyst identified GSK-3β as the most crucial gene in the PI3K-AKT/mTOR pathway in the hippocampus of ASD. Furthermore, we found that IL-6 upregulated the expression of GSK-3β in HT22 cells by upregulating GRP-GRPR. Our findings suggest that IL-6 can enhance the activation of PI3K-AKT/mTOR-GSK-3β in hippocampal neurons of ASD mice by upregulating GRPR. Graphical Abstract

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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IL-6 Enhances the Activation of PI3K-AKT/mTOR-GSK-3β by Upregulating GRPR in Hippocampal Neurons of Autistic Mice

Li,

Wang,

et al. 2024

J Neuroimmune Pharmacol

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“…The cerebellar tissue obtained from the offspring of MIA mice was previously identified as ASD. 12 Briefly, mice were mated overnight, and females were checked every morning for seminal plugs, recorded as embryonic Day 0.5 (E0.5). On E12.5, pregnant mice were weighed and injected with a single dose of poly(I:C) (20 mg/kg) (#P9582, Sigma).…”

Section: Methodsmentioning

confidence: 99%

“…Cerebellar tissues of ASD mice were obtained from previously obtained MIA mouse models. 12 Total RNA from the entire cerebellum of ASD mice in the MIA model (6 weeks, n = 3) was extracted using TRIzol Reagent (Invitrogen) and cDNA was synthesized using the RevertAid First Strand cDNA Synthesis Kit (Thermo Fisher Scientific). qRT-PCR was performed using a SYBR Green real-time PCR kit (Toyobo, Osaka, Japan) on a LightCycler (Bio-Rad Laboratories, Hercules, CA, USA).…”

Section: Methodsmentioning

confidence: 99%

Identification and Analysis of ZIC-Related Genes in Cerebellum of Autism Spectrum Disorders

Li,

Cui,

et al. 2024

NDT

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Objective Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder with significant genetic heterogeneity. The ZIC gene family can regulate neurodevelopment, especially in the cerebellum, and has been implicated in ASD-like behaviors in mice. We performed bioinformatic analysis to identify the ZIC gene family in the ASD cerebellum. Methods We explored the roles of ZIC family genes in ASD by investigating (i) the association of ZIC genes with ASD risk genes from the Simons Foundation Autism Research Initiative (SFARI) database and ZIC genes in the brain regions of the Human Protein Atlas (HPA) database; (ii) co-expressed gene networks of genes positively and negatively correlated with ZIC1, ZIC2, and ZIC3, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment, and receiver operating characteristic (ROC) curve analysis of genes in these networks; and (iii) the relationship between ZIC1, ZIC2, ZIC3, and their related genes with cerebellar immune cells and stromal cells in ASD patients. Results (i) ZIC1, ZIC2, and ZIC3 were associated with neurodevelopmental disorders and risk genes related to ASD in the human cerebellum and (ii) ZIC1, ZIC2, and ZIC3 were highly expressed in the cerebellum, which may play a pathogenic role by affecting neuronal development and the cerebellar internal environment in patients with ASD, including immune cells, astrocytes, and endothelial cells. (iii) OLFM3, SLC27A4, GRB2, TMED1, NR2F1, and STRBP are closely related to ZIC1, ZIC2, and ZIC3 in ASD cerebellum and have good diagnostic accuracy. (iv) ASD mice in the maternal immune activation model demonstrated that Zic3 and Nr2f1 levels were decreased in the immune-activated cerebellum. Conclusion Our study supports the role of ZIC1, ZIC2, and ZIC3 in ASD pathogenesis and provides potential targets for early and accurate prediction of ASD.

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Docosahexaenoic acid ameliorates autistic‐like behaviors by inhibiting oxidative stress and inflammatory response in neonatal maternal separation rats

Xu,

Yuan,

et al. 2024

Pediatric Discovery

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Autism spectrum disorder (ASD) is a pervasive neurodevelopmental disorder characterized by impaired social interactions and communication, repetitive, or stereotyped behavior. Docosahexaenoic acid (DHA), an essential polyunsaturated fatty acid, has been demonstrated to exert anti‐oxidative stress and anti‐inflammatory properties, while also promoting myelin development and neural differentiation and development. However, it remains uncertain whether DHA can ameliorate autistic‐like behaviors, and if so, the underlying mechanisms are still unclear. Here, we established a neonatal maternal separation (NMS) rat model and treated it with DHA (80 mg/kg/day, i.p.). The results showed DHA treatment significantly alleviated autism‐like behaviors in the NMS rats during their juvenile period. Subsequently, we employed network pharmacology analysis and molecular docking methods to screen potential targets of DHA in ASD therapy. Through Gene Ontology, Kyoto Encyclopedia of Genes and Genomes, and Wikipedia enrichment analysis, we identified anti‐oxidative stress, anti‐inflammatory and JNK signaling pathway that might be associated with DHA‐mediated improvement of autistic‐like behaviors. Furthermore, western blotting assays showed DHA significantly downregulated the expression levels of p‐JNK and c‐JUN, while upregulating the expression levels of NRF2, HO‐1, SOD1, and CAT. In addition, enzyme‐linked immunosorbent assay results showed DHA effectively reduced the production of pro‐inflammatory factors, such as TNF‐α, IL‐6, and IL‐1β. Collectively, our study predicted and validated that DHA exhibits the potential to improve autistic‐like behaviors induced by NMS in rats by suppressing JNK activation and inhibiting oxidative stress and inflammatory response. These findings suggest that DHA may be a potential therapeutic agent for the treatment of ASD.

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JUN and PDGFRA as Crucial Candidate Genes for Childhood Autism Spectrum Disorder

Cited by 12 publications

References 77 publications

IL-6 Enhances the Activation of PI3K-AKT/mTOR-GSK-3β by Upregulating GRPR in Hippocampal Neurons of Autistic Mice

IL-6 Enhances the Activation of PI3K-AKT/mTOR-GSK-3β by Upregulating GRPR in Hippocampal Neurons of Autistic Mice

Identification and Analysis of ZIC-Related Genes in Cerebellum of Autism Spectrum Disorders

Docosahexaenoic acid ameliorates autistic‐like behaviors by inhibiting oxidative stress and inflammatory response in neonatal maternal separation rats

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