Abstract
The Autism Spectrum Disorder (ASD) consists of a prevalent and heterogeneous group of neurodevelopmental diseases representing a severe burden to affected individuals and their caretakers. Despite substantial improvement towards understanding of ASD etiology and pathogenesis, as well as increased social awareness and more intensive research, no effective drugs have been successfully developed to resolve the main and most cumbersome ASD symptoms. Hence, finding better treatments, which may act as “disease-modifying” agents, and novel biomarkers for earlier ASD diagnosis and disease stage determination are needed. Diverse mutations of core components and consequent malfunctions of several cell signaling pathways have already been found in ASD by a series of experimental platforms, including genetic associations analyses and studies utilizing pre-clinical animal models and patient samples. These signaling cascades govern a broad range of neurological features such as neuronal development, neurotransmission, metabolism, and homeostasis, as well as immune regulation and inflammation. Here, we review the current knowledge on signaling pathways which are commonly disrupted in ASD and autism-related conditions. As such, we further propose ways to translate these findings into the development of genetic and biochemical clinical tests for early autism detection. Moreover, we highlight some putative druggable targets along these pathways, which, upon further research efforts, may evolve into novel therapeutic interventions for certain ASD conditions. Lastly, we also refer to the crosstalk among these major signaling cascades as well as their putative implications in therapeutics. Based on this collective information, we believe that a timely and accurate modulation of these prominent pathways may shape the neurodevelopment and neuro-immune regulation of homeostatic patterns and, hopefully, rescue some (if not all) ASD phenotypes.
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Abbreviations
- β-TrCP:
-
Beta-transducin repeat-containing protein
- ADH:
-
Alcohol dehydrogenase
- AKT:
-
Protein kinase B (PKB)
- ALDH:
-
Retinaldehyde dehydrogenase
- ALDH1A2:
-
ALDH isoform 1A2
- AMPA:
-
α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid
- ASD:
-
Autism spectrum disorder
- APC:
-
Adenomatous polyposis coli
- ATP:
-
Adenosine triphosphate
- BCL2:
-
B-cell CLL/lymphoma 2 apoptosis regulator
- BCL9:
-
B-cell CLL/lymphoma 9 transcription co-activator
- BDNF:
-
Brain-derived neurotrophic factor
- BMP:
-
Bone morphogenetic protein
- BRAF :
-
Proto-oncogene B-Raf encoding gene
- CBP:
-
CREB(cAMP response element)-binding protein
- CDC:
-
Centers for Disease Control and Prevention (USA)
- CDH7/8/9:
-
Chromodomain helicase DNA binding protein 7/8/9
- CEP290:
-
Centrosomal protein of 290 kDa
- CK1α:
-
Casein kinase 1α
- CNS:
-
Central nervous system
- CSF:
-
Cerebrospinal fluid
- CTNF:
-
Ciliary neurotrophic factor
- CTNNB1 :
-
Catenin beta 1 gene (β-catenin gene)
- Cyp26:
-
Cytochrome P450 enzyme family 26
- Dhh:
-
Desert Hedgehog
- DISC1:
-
Disrupted in schizophrenia 1
- DNMT:
-
DNA methyltransferase
- DKK:
-
Dickkopf
- DSM-5:
-
Diagnostic and statistical manual of mental disorders 5th edition
- Dvl:
-
Disheveled
- DYRK1B:
-
Dual specificity tyrosine phosphorylation regulated kinase 1B
- EIF4E :
-
Eukaryotic translation initiation factor 4E gene
- EGF:
-
Epidermal growth factor
- EGFR:
-
Epidermal growth factor receptor
- EPHA7 :
-
Ephrin type-A receptor 7 gene
- ERK/MAPK/MEK:
-
Mitogen-activated protein kinase
- FDA:
-
Food and Drug Administration
- FMRP:
-
Fragile X mental retardation protein
- FXS:
-
Fragile X syndrome
- FZD:
-
Frizzled (family of G protein-coupled receptors)
- GABA:
-
Gamma-amino butyric acid
- GDF:
-
Growth and differentiation factor
- Gli:
-
Glioma-associated oncogene/transcription factor
- GM-CSF:
-
Granulocyte–macrophage colony-stimulating factor
- Grb2:
-
Growth factor receptor-bound protein
- GSK-3β:
-
Glycogen synthase kinase 3β
- Hh:
-
Hedgehog
- HOX:
-
Homeobox
- HRAS :
-
HRas GTPase gene
- HTR2C :
-
Hydroxytryptamine (serotonin) receptor (human, X chromosomal) gene
- IκB:
-
Inhibitor of nuclear factor kappa-B
- I-SMADs:
-
Inhibitory SMADs
- IGF-1:
-
Insulin-like growth factor 1
- IFN-γ:
-
Interferon gamma
- IL:
-
Interleukin
- Ihh:
-
Indian Hedgehog
- IKKα:
-
IκB kinase alpha
- IKKβ:
-
IκB kinase beta
- IKKγ:
-
IκB kinase gamma
- iNOS:
-
Inducible nitric oxide synthase
- iPSC:
-
Induced pluripotent stem cell
- JAK:
-
Janus kinase
- KRAS:
-
Kirsten rat sarcoma viral oncogene homolog
- LEF:
-
Lymphoid enhancer factor
- LOF:
-
Loss of function
- LRP5/6:
-
Lipoprotein receptor-related protein 5/6
- MeCP2:
-
Methyl-CpG-binding protein 2
- MEK1/2 :
-
Mitogen-activated protein kinase 1 or 2 gene
- mTOR:
-
Mammalian target of rapamycin
- mTORC1:
-
MTOR Complex 1
- mTORC2:
-
MTOR Complex 2
- NFI:
-
Neurofibromatosis Type I
- NF-κB:
-
Nuclear factor kappa B
- NIK:
-
NF-κB inducing kinase
- NMDA:
-
N-Methyl-d-aspartate
- NPC:
-
Neural precursor/progenitor cell
- p300:
-
E1A binding protein p300, transcription co-activator
- Ptch1:
-
Patched 1
- PCDH20 :
-
Protocadherin-20 gene
- PI3K:
-
Phosphoinositide 3-kinase
- PIP2:
-
Phosphatidylinositol 4,5-bisphosphate
- PIP3:
-
Phosphatidylinositol 3,4,5-bisphosphate
- PKC:
-
Protein kinase C
- PTEN:
-
Phosphatase and tensin homolog
- RA:
-
Retinoic acid
- RAI1:
-
Retinoic acid inducible
- RAR:
-
Retinoic acid receptor
- RARE:
-
Retinoic acid response element
- RAS:
-
Rat sarcoma viral oncogene homolog
- RAF1 :
-
RAF proto-oncogene serine/threonine-protein kinase gene
- RDH:
-
Retinol dehydrogenases
- RelA:
-
Nuclear factor NF-kappa B p65 subunit
- RelB:
-
RELB proto-oncogene, NF-κB Subunit
- RERE :
-
Arginine-glutamic acid dipeptide repeats
- RERE:
-
Arginine-glutamic acid dipeptide repeats encoded nuclear receptor coregulator
- RHD:
-
Rel homology domain
- RHEB:
-
Ras homolog enriched in brain
- ROR:
-
Retinoic acid-related orphan receptors
- RORA :
-
Retinoic acid-related orphan receptor α gene
- RORE:
-
ROR response elements
- R-SMADs:
-
Receptor-regulated SMADs
- RXR:
-
Retinoid X receptor
- S6K:
-
Ribosomal protein S6 kinase
- SEMA3A :
-
Semaphorin-3A gene
- SFARI:
-
Simons foundation autism research initiative
- SFRP:
-
Secreted frizzled-related proteins
- SGK1:
-
Serine/threonine-protein kinase
- Shh:
-
Sonic Hedgehog
- SLOS:
-
Smith-Lemli-Opitz syndrome
- SMO:
-
Smoothened
- SNP:
-
Single-nucleotide polymorphism
- SOS:
-
Son of sevenless
- SOCS:
-
Suppressors of cytokine signaling proteins
- SSRI:
-
Selective serotonin reuptake inhibitor
- STAT:
-
Signal transducer and activator of transcription
- SuFu:
-
Suppressor of fused
- TAK1:
-
Mitogen-activated protein kinase 7 (MAP3K7)
- TCF:
-
T-cell factor
- TET:
-
Ten eleven translocation
- TF:
-
Transcription factor
- Th:
-
T-helper cell
- TGF-β:
-
Transforming growth factor beta
- TGFBR1:
-
Type 1 TGF-β receptor
- TGFBR2:
-
Type 2 TGF-β receptor
- TLR:
-
Toll-like receptor
- TNF:
-
Tumor necrosis factor
- TNFR:
-
Tumor necrosis factors receptors
- Treg:
-
Regulatory T-cell
- TSC1/2:
-
Tuberous sclerosis complex 1 or 2
- Tyk2:
-
Tyrosine kinase 2
- UBE3A:
-
Ubiquitin-protein Ligase E3 = E6AP ubiquitin-protein ligase
- VA:
-
Valproic acid
- Wnt:
-
Wingless-type/Int-1 (known as: INT1 and related gene products)
- WIF:
-
Wnt inhibiting factor
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Acknowledgements
We are grateful to the Department of Biochemistry of the Institute of Chemistry (IQ) of the University of São Paulo (USP, São Paulo, Brazil) for the academic support and opportunity to write this review.
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R.G.C. was supported by a Visiting Professor grant (Edital 02/2019, PrInt USP/CAPES) from University of São Paulo (USP) and CAPES (Federal Agency for Superior Education and Training), Brazil.
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Manuscript conceptualization: RGC. Drafting the text: JB, GD, MCSB, RBA, RRA, ALPA, DP. Preparing figures: JB, GD, MCSB. Manuscript editing and formatting: JB, GD, MCS, RGC, HU. Manuscript revision: RGC, MCS, HU.
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Baranova, J., Dragunas, G., Botellho, M.C.S. et al. Autism Spectrum Disorder: Signaling Pathways and Prospective Therapeutic Targets. Cell Mol Neurobiol 41, 619–649 (2021). https://doi.org/10.1007/s10571-020-00882-7
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DOI: https://doi.org/10.1007/s10571-020-00882-7