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Understanding Abnormal SMO-SHH Signaling in Autism Spectrum Disorder: Potential Drug Target and Therapeutic Goals

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Abstract

Autism is a multifactorial neurodevelopmental condition; it demonstrates some main characteristics, such as impaired social relationships and increased repetitive behavior. The initiation of autism spectrum disorder is mostly triggered during brain development by the deregulation of signaling pathways. Sonic hedgehog (SHH) signaling is one such mechanism that influences neurogenesis and neural processes during the development of the central nervous system. SMO-SHH signaling is also an important part of a broad variety of neurological processes, including neuronal cell differentiation, proliferation, and survival. Dysregulation of SMO-SHH signaling leads to many physiological changes that lead to neurological disorders such as ASD and contribute to cognitive decline. The aberrant downregulation of SMO-SHH signals contributes to the proteolytic cleavage of GLI (glioma-associated homolog) into GLI3 (repressor), which increases oxidative stress, neuronal excitotoxicity, neuroinflammation, and apoptosis by suppressing target gene expression. We outlined in this review that SMO-SHH deregulation plays a crucial role in the pathogenesis of autism and addresses the current status of SMO-SHH pathway modulators. Additionally, a greater understanding of the SHH signaling pathway is an effort to improve successful treatment for autism and other neurological disorders.

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Abbreviations

AD:

Alzheimer’s disease

Akt:

Protein kinase B

ALS:

Amyotrophic lateral sclerosis

AML:

Acute myeloid leukemia

ASD:

Autism spectrum disorder

BBB:

Blood–brain barrier

BDNF:

Brain-derived neurotrophic factor

Boc:

Brother of cell adhesion molecule-related

CK1:

Casein kinase 1

CML:

Chronic myeloid leukemia

CNS:

Central nervous system

CNV’s:

Copy number variations

DHH:

Desert Hedgehog

FGSA:

Fluorinated glucocorticoid SMO agonist

GLI:

Glioma-associated homolog

GLIR:

Glioma-associated homolog repressor

GRK2:

G protein-coupled receptor kinase-2

GSK3:

Glycogen synthase kinase-3

Hh-Ag:

Hedgehog agonist

ICV:

Intracerebroventicular

IHH:

Indian Hedgehog

KDa:

KiloDalton

laBCC’s:

Locally advanced basal cell carcinoma

MAPK3:

Mitogen-activated protein 3

mBCC’s:

Metastatic basal cell carcinoma

MCAO:

Middle cerebral artery occlusion

mRNA:

Messenger riboneuclic acid

MS:

Multiple sclerosis

NPC’s:

Neural progenitor cells

NSC’s:

Neural stem cells

OFR:

Oxidative free radicals

PD:

Parkinson’s disease

PKA:

Protein kinase A

PPA:

Propionic acid

PTCH1:

Patched-1

RMS:

Rhabdomyosarcoma

ROS:

Reactive oxidative species

SAG:

SHH agonist

SGZ:

Subgranular zone

SVZ:

Subventricular zone

SANT:

SHH antagonist

SHH:

Sonic hedgehog

SIP:

Sphingosine 1-phosphate

SKN:

Skinny hedgehog acetyltransferase

SMO:

Smoothened

SNP’s:

Single-nucleotide polymorphism

SUFU:

Suppressor of fused

UBE3A:

Ubiquitin-protein ligase E3A

VEGF:

Vascular endothelial growth factor

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Acknowledgements

The authors express their gratitude to Chairman, Mr. Parveen Garg, and Director, Dr. G.D.Gupta, ISF College of Pharmacy, Moga (Punjab), India, for their great vision and support.

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Ms. SR (First Author)—M.Pharm, Neuropharmacology Division, Department of Pharmacology—Contribution: Library searches and assembling relevant literature, original writing, compilation, and critical review of the manuscript. Dr. SM (Corresponding Author)—PhD, M.Pharm, Neuropharmacology Division, Department of Pharmacology—Contribution: Conceived the original idea, Guide, and compilation of all manuscript data.

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Correspondence to Sidharth Mehan.

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Rahi, S., Mehan, S. Understanding Abnormal SMO-SHH Signaling in Autism Spectrum Disorder: Potential Drug Target and Therapeutic Goals. Cell Mol Neurobiol 42, 931–953 (2022). https://doi.org/10.1007/s10571-020-01010-1

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