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

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.

Keywords: Autism; GLI; Neural cell differentiation; Neuronal cell proliferation; Smoothened; Sonic hedgehog signaling.

Fig. 1

Etiological factors and sign/symptoms of autism. Different causative variables are responsible for the multiple signs/symptoms, including motor and non-motor alterations with other behavioral abnormalities, as discussed in the above figure.

Fig. 2

a Pathomechanism of autism. In autism pathogenesis, multiple factors have been involved, such as genetic aberrations, environmental contaminants, nutritional disorders, and intestinal defects, including gut microbiota dysfunction and maternal abnormalities, and impacted significant brain regions, including basal ganglia and hippocampus. Dysfunctions in such areas contribute to free-radical production, neurotransmitter alterations, neuroexcitation, and mitochondrial and immunological dysfunction leading to the neuronal cell death. b Current available/approachable treatment of autism. The neuronal failure caused by the multiple causative variables contributes to different changes in behavior. Different drug therapies are used to resolve these causes. The medications in the blue box represent the approved medications by the FDA. In contrast, the purple box is the approachable autism treatments currently used for the symptomatic relief for the behavioral abnormalities

Fig. 2

a Pathomechanism of autism. In autism pathogenesis, multiple factors have been involved, such as genetic aberrations, environmental contaminants, nutritional disorders, and intestinal defects, including gut microbiota dysfunction and maternal abnormalities, and impacted significant brain regions, including basal ganglia and hippocampus. Dysfunctions in such areas contribute to free-radical production, neurotransmitter alterations, neuroexcitation, and mitochondrial and immunological dysfunction leading to the neuronal cell death. b Current available/approachable treatment of autism. The neuronal failure caused by the multiple causative variables contributes to different changes in behavior. Different drug therapies are used to resolve these causes. The medications in the blue box represent the approved medications by the FDA. In contrast, the purple box is the approachable autism treatments currently used for the symptomatic relief for the behavioral abnormalities

Fig. 3

Schematic overview of SMO-SHH signaling pathway. This figure provides a schematic overview of the ON- and OFF-state SMO-SHH pathway. Under the ON state, SHH binds to the Patch1 receptor and eliminates the inhibition induced by Patch1 from the SMO receptor. This makes SMO open to activated Gli1, contributing to the activation of the transcription process in the future. The SHH is not available for binding on Patch1 in the OFF state, and SMO remains in the deactivated state. This schematic representation shows the SMO-SHH

Fig. 4

Role of SHH in autism. Under stress conditions, SHH ligand does not bind to the receptor of Patch1, which leaves SMO inaccessible for GLI1 activation. GLI 3 (repressor) becomes activated under these conditions and contributes to irregular signaling. The schematic figure represents that the elevated GLI 3 resulted in downregulated SMO-SHH signaling, which causes oxidative stress, neuronal excitotoxicity, neuronal apoptosis, and neuron-inflammation to increase abnormally. This alteration affects the survival of the cells and triggers an unexpected increase in Autism-related neuronal cell death