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Review
. 2023 Jan 17;24(3):1819.
doi: 10.3390/ijms24031819.

Autism Spectrum Disorder: Neurodevelopmental Risk Factors, Biological Mechanism, and Precision Therapy

Ling Wang  1 , Binquan Wang  1 , Chunyan Wu  1 , Jie Wang  1 , Mingkuan Sun  1
Affiliations
Review

Autism Spectrum Disorder: Neurodevelopmental Risk Factors, Biological Mechanism, and Precision Therapy

Ling Wang et al. Int J Mol Sci. .

Abstract

Autism spectrum disorder (ASD) is a heterogeneous, behaviorally defined neurodevelopmental disorder. Over the past two decades, the prevalence of autism spectrum disorders has progressively increased, however, no clear diagnostic markers and specifically targeted medications for autism have emerged. As a result, neurobehavioral abnormalities, neurobiological alterations in ASD, and the development of novel ASD pharmacological therapy necessitate multidisciplinary collaboration. In this review, we discuss the development of multiple animal models of ASD to contribute to the disease mechanisms of ASD, as well as new studies from multiple disciplines to assess the behavioral pathology of ASD. In addition, we summarize and highlight the mechanistic advances regarding gene transcription, RNA and non-coding RNA translation, abnormal synaptic signaling pathways, epigenetic post-translational modifications, brain-gut axis, immune inflammation and neural loop abnormalities in autism to provide a theoretical basis for the next step of precision therapy. Furthermore, we review existing autism therapy tactics and limits and present challenges and opportunities for translating multidisciplinary knowledge of ASD into clinical practice.

Keywords: ASD animal model; autism spectrum disorder (ASD); neurobiological mechanisms; neurocircuit mechanisms; therapeutic strategies.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Translation cycle of ASD research. Epidemiological studies of ASD patients can identify abnormal genes and underlying risk factors, including genetic mutations, copy number variations (CNVs), environmental exposures, and maternal immune activation during pregnancy. Based on these data, different animal models will be developed and characterized for their variations. A comprehensive analysis of animal models combined with human pathology to understand the pathogenesis of ASD holds promise as a new therapeutic strategy to feed back to patients.
Figure 2
Figure 2
The Synaptic signaling pathway are mechanistically targeted. Wnt pathway activation of cytoplasmic β-catenin is degraded by the proteasome after phosphorylation by GSK-3β. When GSK-3β fails to phosphorylate β-catenin, cytoplasmic β-catenin accumulates in the nucleus and binds to the TCF/LEF complex and CHD8 factor to activate transcription of target genes and enhances synaptic plasticity and neuronal protection. Both ERK/MAPK and PI3K-AKT-mTOR signaling pathways can be activated in response to TrKB stimulation Activation of L-type voltage-sensitive calcium channels (LVSCCs) triggers calcium inward flow and induces calcium-dependent signaling molecules and the Ras/ERK pathway, which are involved in transcriptional regulation. Mutations in proteins involved in translational regulation include PTEN, MECP2, UBE3A and TSC1/TSC2. These genes are marked in red.
Figure 3
Figure 3
Methylation and acetylation modifications associated with ASD. DNA methylation frequently results in transcriptional repression or even gene silence in impacted genes. MECP2 binds to methylated CpG sites in gene promoters and binds to chromatin silencing complexes, inhibiting gene expression; protein modifications and chromatin remodeling in the acetylation group contribute to transcriptional activation or inactivation and chromatin packaging.
Figure 4
Figure 4
A network of epigenetic post-translational modifications associated with ASD pathophysiology. (A) Ras inactivation is generally caused by neurofibrillar proteins encoded by NF1. Neurofibrillary protein mutations in neurofibromatosis 1 cause excessive activation of the Ras/ERK and PI3K signaling pathways, affecting and inhibiting translation of proteins encoded by genes associated with neurodegenerative diseases in autism. (B) USP8 is required for synaptic function by stabilizing Shank family proteins to prevent degradation. UBE3A regulates synaptic activity by targeting XIAP ubiquitination. (C) FMRP activity-dependent SUMOylation is a critical step in the separation of FMRP from dendritic mRNA particles, which regulates spine elimination and maturation. CRMP2 is a SUMO substrate that reduces Ca2+ entry via the presynaptic voltage-gated Ca2+ channel CaV2 in a dynamic manner. 2. CRMP2 SUMOylation is also thought to regulate membrane expression in the sodium channel NaV1.7. Syntaxin-1A SUMOylation is induced by NMDAR activation, resulting in decreased binding to SNAP-25 and serving as a key presynaptic modulator of vesicular endocytosis.
Figure 5
Figure 5
Potential therapy strategies for autism spectrum diseases. The small gray circles represent components of current ASD treatment strategies. Pharmacological treatments, nonpharmacological treatments, cellular and exosomal therapies, gene therapy, and potential emerging therapeutics are all covered. The large blue circles represent the benefits and drawbacks of various ASD therapy options for specific symptoms. Specific developments in emerging treatment methods are also discussed.
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