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Review
. 2021 Jan;18(1):265-283.
doi: 10.1007/s13311-020-00968-6. Epub 2020 Nov 19.

Overlapping Molecular Pathways Leading to Autism Spectrum Disorders, Fragile X Syndrome, and Targeted Treatments

Maria Jimena Salcedo-Arellano #  1   2   3 , Ana Maria Cabal-Herrera #  4 , Ruchi Harendra Punatar  5   6 , Courtney Jessica Clark  5   6 , Christopher Allen Romney  5   6 , Randi J Hagerman  7   8
Affiliations
Review

Overlapping Molecular Pathways Leading to Autism Spectrum Disorders, Fragile X Syndrome, and Targeted Treatments

Maria Jimena Salcedo-Arellano et al. Neurotherapeutics. 2021 Jan.

Abstract

Autism spectrum disorders (ASD) are subdivided into idiopathic (unknown) etiology and secondary, based on known etiology. There are hundreds of causes of ASD and most of them are genetic in origin or related to the interplay of genetic etiology and environmental toxicology. Approximately 30 to 50% of the etiologies can be identified when using a combination of available genetic testing. Many of these gene mutations are either core components of the Wnt signaling pathway or their modulators. The full mutation of the fragile X mental retardation 1 (FMR1) gene leads to fragile X syndrome (FXS), the most common cause of monogenic origin of ASD, accounting for ~ 2% of the cases. There is an overlap of molecular mechanisms in those with idiopathic ASD and those with FXS, an interaction between various signaling pathways is suggested during the development of the autistic brain. This review summarizes the cross talk between neurobiological pathways found in ASD and FXS. These signaling pathways are currently under evaluation to target specific treatments in search of the reversal of the molecular abnormalities found in both idiopathic ASD and FXS.

Keywords: Autism spectrum disorders; ERK/MAPK; Wnt; endocannabinoid system; fragile X syndrome; mTOR; neurodevelopmental disorders; retinoic acid; signaling cross talk; targeted treatments.

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Figures

Fig. 1
Fig. 1
Canonical Wnt signaling pathway and activators. (a) Wnt proteins are cysteine-rich glycolipoproteins that act as ligands to receptors of the Wnt pathway. When Wnt is bound to the Frizzled receptor and its coreceptors, such as lipoprotein receptor-related protein (LRP), cytoplasmic disheveled (Dsh) protein is recruited and activated. Dsh regulates the inactivation of the destruction complex. This allows for β-catenin to be released from the destruction complex. Stabilized β-catenin can then enter the nucleus, displace Groucho/transducin-like enhancer of split (TLE) (not shown) and activate the transcription of Wnt target genes. (b) In the absence of Wnt, β-catenin is degraded by the destruction complex that includes molecules such as glycogen synthase kinase 3 beta (GSK-3β), casein kinase 1 alpha (CK1α), adenomatous polyposis coli (APC), and axin. The destruction complex phosphorylates β-catenin and facilitates ubiquitination by β-TrCP, leading to β-catenin’s proteosomal degradation. Dsh = disheveled; GSK-3β = glycogen synthase kinase 3 beta; APC = adenomatosis polyposis coli; LRP = lipoprotein receptor-related proteins; β-TrCP = beta-transducin repeats-containing proteins; SSRI’s = selective serotonin reuptake inhibitors; VA = valproic acid. Activators of the Wnt pathway: Lithium inhibits GSK-3β and therefore activates the Wnt pathway. Selective serotonin reuptake inhibitors (SSRIs) and valproic acid (VA) act by stimulating the expression of Wnt-targeted genes
Fig. 2
Fig. 2
Metformin and the PI3K/AKT/mTOR pathway. Proposed mechanisms for metformin’s regulation of the PI3K/AKT/mTOR pathway. Black arrows represent activation pathways whereas red lines represent inhibitory pathways. IGF-1 = insulin-like growth factor-1; IGF-1R = insulin-like growth factor-1 receptor; IRS = insulin receptor substrate; PI3K = phosphoinositide 3-kinase; PIP2 = phosphatidylinositol-4,5-bisphosphate; PIP3 = phosphatidylinositol-4,5-triphosphate; PTEN = phosphatase and tensin homolog; PDK1 = phosphoinositide-dependent kinase 1; PKB = protein kinase B or Akt; TSC1 = tuberous sclerosis complex 1 (hamartin); TSC2 = tuberous sclerosis complex 2 (tuberin); Rheb = Ras homolog enriched in brain; mTOR = mammalian target of rapamycin; 4E-BP1 = eukaryotic initiation factor 4E binding protein 1; eIF4E = eukaryotic translation initiation factor 4E; p70S6K = p70 ribosomal protein S6 kinase; S6K = S6 kinase; AMP = adenosine monophosphate; AMPK = AMP-activated protein kinase; AAs = amino acids; Rags = Rag GTPases
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References

    1. Zablotsky B, Black LI, Maenner MJ, Schieve LA, Danielson ML, Bitsko RH, et al. Prevalence and trends of developmental disabilities among children in the United States: 2009–2017. J Pediatr. 2019;144(4):e20190811. doi: 10.1542/peds.2019-0811%. - DOI - PMC - PubMed
    1. Maenner M, Shaw K, Baio J, et al. Prevalence of autism spectrum disorder among children aged 8 years — Autism and Developmental Disabilities Monitoring Network, 11 sites, United States. MMWR Surveill Summ. 2020. 2016;69:1–12. 10.15585/mmwr.ss6904a1. - PMC - PubMed
    1. American Psychiatric Association. DSM-5 Task Force. Diagnostic and statistical manual of mental disorders : DSM-5. 5th ed. Washington, DC.: American Psychiatric Association; 2013.
    1. Anderson DK, Oti RS, Lord C, Welch K. Patterns of growth in adaptive social abilities among children with autism spectrum disorders. J Abnorm Child Psychol. 2009;37(7):1019–34. doi: 10.1007/s10802-009-9326-0. - DOI - PMC - PubMed
    1. Brignell A, Chenausky KV, Song H, Zhu J, Suo C, Morgan AT. Communication interventions for autism spectrum disorder in minimally verbal children. Cochrane Database Syst Rev. 2018;11(11):CD012324-CD. doi: 10.1002/14651858.CD012324.pub2. - DOI - PMC - PubMed

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