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Multiple Signaling Neurodevelopmental Pathways
Understanding the autistic brain and the involvement of genetic, non-genetic, and numerous signaling pathways in the etiology and pathophysiology of autism spectrum disorder (ASD) is complex, as is evident from various studies. Apart from multiple developmental disorders of the brain, autistic subjects show a few characteristics like impairment in social communications related to repetitive, restricted, or stereotypical behavior, which suggests alterations in neuronal circuits caused by defects in various signaling pathways during embryogenesis. Most of the research studies on ASD subjects and genetic models revealed the involvement of mutated genes with alterations of numerous signaling pathways like Wnt, hedgehog, and Retinoic Acid (RA).
2. Types of Autism Spectrum Disorder
Requires extensive medical support
Severe impairment in verbal and non-verbal communication; a deficit in social interactions; less response to social overtures (e.g., rarely starts an interaction if they have some words of intelligible speech and respond only to direct social overtures.
Rigid behavior; extreme problems coping with change; repetitive or restricted behavior marked by interferences in body functioning in all spheres; great difficulty changing action or focus.
Requires medical support
Marked impairment in verbal and non-verbal communication; a deficit in social interaction even with support; minimum responses to social overtures like simple spoken sentences; less interest in interaction, and odd behavior in non-verbal communication
Rigid behavior; difficulty coping with change, repetitive or restricted behavior affecting various functions in different contexts; trouble changing action or focus.
Noticeable impairments in social interaction without support; problems initiating interactions with people and appears to have less interest in social communication (e.g., affected person speaks full sentences with others but to-and-fro conversation fails and attempts to make friends typically not successful and odd),
Rigid behavior causes difficulty with functioning in several contexts; problems switching from one activity to another; a deficit in behavior while organizing and planning inhibits independence.
3. Etiology and Pathophysiology of ASD
4. Impairment of Developmental Pathways
4.1. Wnt Protein and β-Catenin Signaling Pathways
4.2. Hedgehog Signaling Pathway
4.3. Retinoic Acid (RA) Signaling Pathway
Retinoic acid can affect various developmental genes that contain retinoic acid response elements (RARE) together with their regulatory spaces. This role of RA suggests interconnections among neurodevelopmental disorders and RA signaling pathways. During embryonic development, retinoic acid helps regulate a set of HOX (homeobox) genes that, during embryogenesis, shapes the upper-body pattern both anteriorly and posteriorly and is involved in brain patterning. RA is engaged in neural-cell differentiation involving dopaminergic and GABAergic neurons. It is also a key induction component (together with sonic hedgehog) for the differentiation of motor neurons from pluripotent stem cells . Moreover retinoic acid is also important for the normal functioning of motor neurons. It was also reported that RA is important for neural migration and neurogenesis in the granular zone of the hippocampus, sub-ventricular zone, and olfactory bulb . Retinol concentration in adequate amount is required for normal functioning of RA signaling pathway presuming that all the enzymes related to RA pathway and nuclear factors work accordingly. Figure 3 represents the synthesis of retinoic acid and the retinoic acid signaling pathway. The deficiency of retinol is one of the major causes of decreased intracellular RA signaling. Some studies demonstrated that the deficiency of retinol in rats during pregnancy decreases RA receptor expression (RAR, beta isoform) in the hypothalamus, causing autistic-like symptoms in the neonates . Interestingly, a lower level of retinol was detected in some autistic subjects when compared with the normal control group in China, which was possibly a synergistic factor in ASD symptom development . Retinol supplements can activate RAR expression and lessen ASD symptoms. The important metabolic step in the RA pathway is the conversion of retinal to retinoic acid with the help of the enzyme (ALDH) retinaldehyde dehydrogenase, which ensures the concentration of RA in the cell. An increase in the degradation rate of this enzyme’s isoform ALDH 1A2 because of over-ubiquitinoylation by the enzyme UBE3A (ubiquitin ligase E3) was established in vitro, and autistic features were observed in mice with an overexpression of UBE3A . The loss of function of UBE3A is related to a neurodevelopmental disorder (Angelman syndrome) showing its importance in brain development . The nuclear receptors for RA have also been involved in ASD pathology. RORs (retinoic acid related orphan receptors) activate transcription of several genes by acting as transcriptional regulators upon retinoic acid-binding. A reduction in ROR gene expression due to hypermethylation was found in autistic subjects. In addition, an immunohistochemical analysis of the postmortem brains of autistic subjects confirmed a lower level of ROR alpha protein . Disruption of the retinoic acid enzymatic production pathway was found to be associated with ASD phenotypes and retinoic acid nuclear receptors, which have also been involved in the pathophysiology of ASD; hence, additional studies have to be performed to establish the correlation between ASD pathogenesis and the involvement of RAR and ROR agonists for autism treatment. Quantitative EEG analysis is another signal-detection tool for diagnosing ASD. The details of the individual characterization of EEG fluctuations in ASD subjects could help examine issues of the brain, which would be useful for observing automatic groupings and random draws of the patient population when analyzing the sensory-processing issues of the brain and the peripheral system .
The entry is from 10.3390/cells10040958
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