Abstract
Intellectual disability (ID) is a pathological condition characterized by limited intellectual functioning and adaptive behaviors. It affects 1–3% of the worldwide population, and no pharmacological therapies are currently available. More than 1000 genes have been found mutated in ID patients pointing out that, despite the common phenotype, the genetic bases are highly heterogeneous and apparently unrelated. Bibliomic analysis reveals that ID genes converge onto a few biological modules, including cytoskeleton dynamics, whose regulation depends on Rho GTPases transduction. Genetic variants exert their effects at different levels in a hierarchical arrangement, starting from the molecular level and moving toward higher levels of organization, i.e., cell compartment and functions, circuits, cognition, and behavior. Thus, cytoskeleton alterations that have an impact on cell processes such as neuronal migration, neuritogenesis, and synaptic plasticity rebound on the overall establishment of an effective network and consequently on the cognitive phenotype. Systems biology (SB) approaches are more focused on the overall interconnected network rather than on individual genes, thus encouraging the design of therapies that aim to correct common dysregulated biological processes. This review summarizes current knowledge about cytoskeleton control in neurons and its relevance for the ID pathogenesis, exploiting in silico modeling and translating the implications of those findings into biomedical research.
Highlights
Intellectual disability (ID) is a heterogeneous group of neurodevelopmental disorders (NDDs), usually diagnosed before the age of 18, characterized by significant limitations in both intellectual functioning (IQ < 70) and adaptive behavior as expressed in conceptual, social, and practical adaptive skills [1]
Strong evidence indicates that cytoskeleton dynamics isaffected by mutations detected in ID (Figure 1B) and other NDDs; in this review, we focus on cytoskeleton regulation in physiological conditions and its dysregulation in the ID context
Alterations in neurites and spine morphology, as well as in neuronal migration properties, have been consistently associated with ID and other NDDs that include ID as a main and recurrent phenotype [84]. These developmental features rely on the proper actin cytoskeleton dynamics, as neurite outgrowth, axonal migration, synaptogenesis, and synaptic plasticity are the result of three main processes: fibrous-actin (F-actin) dynamics, actin–myosin contractility, and F-actin coupling with the extracellular matrix [85,86]
Summary
ID is a heterogeneous group of neurodevelopmental disorders (NDDs), usually diagnosed before the age of 18, characterized by significant limitations in both intellectual functioning (IQ < 70) and adaptive behavior as expressed in conceptual, social, and practical adaptive skills [1]. It affects 1–3% of the worldwide population, depending on the inclusion criteria, with a higher prevalence among males [2,3,4,5]. And behavioral abnormalities were linked to two clusters comprising genes enriched with chromatin-related functions. Based on a wealth of experimental data from animal models and cultured neurons, it is widely accepted that cognitive deficits in ID patients are linked to altered neuronal networking, impaired synaptic plasticity, and excitation/inhibition unbalance in the cerebral cortex and hippocampus, resulting in abnormal information processing [6,7,8,9,10,11]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
