A Subset of Autism-Associated Genes Regulate the Structural Stability of Neurons

Abstract

Autism spectrum disorder (ASD) comprises a range of neurological conditions that affect individuals’ ability to communicate and interact with others. People with ASD often exhibit marked qualitative difficulties in social interaction, communication, and behavior. Alterations in neurite arborization and dendritic spine morphology, including size, shape, and number, are hallmarks of almost all neurological conditions, including ASD. As experimental evidence emerges in recent years, it becomes clear that although there is broad heterogeneity of identified autism risk genes, many of them converge into similar cellular pathways, including those regulating neurite outgrowth, synapse formation and spine stability, and synaptic plasticity. These mechanisms together regulate the structural stability of neurons and are vulnerable targets in ASD. In this review, we discuss the current understanding of those autism risk genes that affect the structural connectivity of neurons. We sub-categorize them into (1) cytoskeletal regulators, e.g., motors and small RhoGTPase regulators; (2) adhesion molecules, e.g., cadherins, NCAM, and neurexin superfamily; (3) cell surface receptors, e.g., glutamatergic receptors and receptor tyrosine kinases; (4) signaling molecules, e.g., protein kinases and phosphatases; and (5) synaptic proteins, e.g., vesicle and scaffolding proteins. Although the roles of some of these genes in maintaining neuronal structural stability are well studied, how mutations contribute to the autism phenotype is still largely unknown. Investigating whether and how the neuronal structure and function are affected when these genes are mutated will provide insights toward developing effective interventions aimed at improving the lives of people with autism and their families.

Clinical and Molecular Characterization of Two Patients with CNTN6 Copy Number Variations

“…In the 3 families reported by Kashevarova et al [2014], ID, psychomotor and growth retardation, microcephaly, and additional dysmorphic features were the common symptoms of CNTN6 CNVs. More recently, it has been suggested that microdeletions and point mutations of the CNTN6 gene may be associated with ASD and ID [Lin et al, 2016;Mercati et al, 2017].…”

Peptide regulation of cofilin activity in the CNS: A novel therapeutic approach for treatment of multiple neurological disorders

“…Furthermore, wild type mice in which cofilin phosphorylation has been inhibited by blocking the LIMK signaling pathway develop the social deficits of the autistic mice, supporting the role of cofilin in the autistic behavior (Duffney et al, 2015). Other autistic mouse models have been developed by expression of mutations in, or gene knock out of, transmembrane proteins linking pre- and post-synaptic compartments (Lin et al, 2016). It remains to be determined if all of these have in common the downstream regulation of cofilin, although for one of these proteins, neuroligin 1, cofilin regulation plays a central role (see section 7 below).…”

STXBP5/tomosyn regulates the small RhoA GTPase to control the dendritic stability of neurons and the surface expression of AMPA receptors

“…Individuals with ASD commonly exhibit difficulties in social communication and interaction, repetitive behaviors, and restricted interests (18). Although ASD exhibits a high degree of genetic heterogeneity, many identified risk genes converge on similar cellular pathways, including those that regulate neurite outgrowth, spine stability, synaptic plasticity, excitatory/inhibitory balance, and trafficking of glutamate receptors (19)(20)(21)(22)(23)(24)(25)(26)(27). Several human genetic studies, including genome-wide association studies and wholeexome sequencing, have linked the deletion, as well as two tomosyn variants (L412V and Y502C) to ASD (28)(29)(30)(31).…”