Circadian clock crosstalks with autism

Abstract

Background: The mechanism underlying autism spectrum disorder (ASD) remains incompletely understood, but researchers have identified over a thousand genes involved in complex interactions within the brain, nervous, and immune systems, particularly during the mechanism of brain development. Various contributory environmental effects including circadian rhythm have also been studied in ASD. Thus, capturing the global picture of the ASD-clock network in combined form is critical.

Methods: We reconstructed the protein-protein interaction network of ASD and circadian rhythm to understand the connection between autism and the circadian clock. A graph theoretical study is undertaken to evaluate whether the network attributes are biologically realistic. The gene ontology enrichment analyses provide information about the most important biological processes.

Results: This study takes a fresh look at metabolic mechanisms and the identification of potential key proteins/pathways (ribosome biogenesis, oxidative stress, insulin/IGF pathway, Wnt pathway, and mTOR pathway), as well as the effects of specific conditions (such as maternal stress or disruption of circadian rhythm) on the development of ASD due to environmental factors.

Conclusion: Understanding the relationship between circadian rhythm and ASD provides insight into the involvement of these essential pathways in the pathogenesis/etiology of ASD, as well as potential early intervention options and chronotherapeutic strategies for treating or preventing the neurodevelopmental disorder.

Keywords: ASD; bioinformatics; circadian rhythmicity; neurodevelopmental diseases; protein-protein interaction network.

FIGURE 1

Protein–protein interaction networks and Venn diagram: (a) APPIN5: This significant network focuses on interactions and highlights hub proteins and their connections related to autism spectrum disorder (ASD); (b) CPPIN2: This network emphasizes circadian clock‐related interactions; (c) combined circadian–autism protein–protein interaction network (CAPPIN): The CAPPIN visualizes comprehensive protein–protein interactions, combining APPIN5 and CPPIN2, showcasing the significant interactions between autism and the circadian clock; (d) Venn diagram of interactions: This diagram provides an overview of the overlaps and unique interaction numbers between these protein interaction networks.

FIGURE 2

The interactome network CPPIN2 is subdivided into clusters of proteins with extensive and robust interactions. Cluster 1 from CPPIN2, which has been extracted from Cytoscape, containing essential circadian genes.

FIGURE 3

The interactome network combined circadian–autism protein–protein interaction network (CAPPIN) is subdivided into clusters of proteins with extensive and robust interactions. Clusters: (a) 1, (b) 10, (c) 12, (d) 30 extracted from Cytoscape.

FIGURE 4

Six‐protein length pathways of combined circadian–autism protein–protein interaction network (CAPPIN) from ARNTL to TCF4 (CPPIN: ARNTL and CSNK1E (hub/bottleneck proteins), AXIN1, CTNNB1, TLE3, TLE4; APPIN: CTNNB1, TCF4). This figure illustrates the 6‐steps pathways within the CAPPIN that connect ARNTL to TCF4. The central role of ARNTL and CSNK1E as hub/bottleneck proteins is highlighted, along with the significant involvement of AXIN1, CTNNB1, TLE3, and TLE4 in these pathways.

FIGURE 5

The most likely pathways of combined circadian–autism protein–protein interaction network (CAPPIN) (5–6–7–8 steps) from ARNTL to TCF4. This figure illustrates the most likely pathways within the CAPPIN, depicting a series of 5–6–7–8 steps that connect ARNTL to TCF4. CAPPIN represents a combined network involving critical proteins such as ARNTL, CSNK1E (hub/bottleneck proteins), and TCF4. These pathways provide valuable insights into the complex protein–protein interactions that underlie the connection between circadian rhythms and autism spectrum disorder (ASD).

FIGURE 6

Mammalian protein signaling pathway with positive and negative feedback loops. This figure illustrates circadian genes and their feedback loops in the regulation of mammalian circadian rhythms, with positive and negative feedback mechanisms. It also highlights the pivotal role of the P53 tumor suppressor gene.