Neuronal Cytoskeleton in Intellectual Disability: From Systems Biology and Modeling to Therapeutic Opportunities

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.

Neurons: The Interplay between Cytoskeleton, Ion Channels/Transporters and Mitochondria

“…Another nosographic entity where cytoskeleton alterations may play a crucial and still underexplored role is ID, which is defined as a pathological condition characterized by limited intellectual functioning and adaptive behaviors, affecting 1–3% of the world’s population, lacking of an efficacious pharmacological treatment [ 133 ]. Further investigations on the role of the cytoskeleton in this regard may shed light not only on the mechanisms leading to this condition, but also define potential precision medicine strategies (e.g., targeted therapies).…”

The Emerging Roles of Long Non-Coding RNAs in Intellectual Disability and Related Neurodevelopmental Disorders

“…For decades, we have concentrated on the coding part of the genome, leaving the large non-coding, but still transcribed, portion aside. Attempts to cluster the ID-risk coding genes into functional categories have led to the recognition of a limited number of neuronal hubs involved in the pathology endophenotype [ 51 ]. Still, a significant fraction of patients with sporadic, syndromic, or non-syndromic ID lacks a genetic and/or molecular explanation.…”

“…The non-genetic causes or con-causes of ID are being heavily investigated [ 44 , 45 , 46 , 47 ]; concerning genetics, research has so far focused on the identification of mutated protein-coding genes inherited in a Mendelian fashion, mainly due to the availability of the exome sequencing derived data from ID patients and trios [ 48 , 49 , 50 , 51 ]. Such continuing effort has led to the identification of more than 200 confirmed ID-causative genes.…”

“…Such continuing effort has led to the identification of more than 200 confirmed ID-causative genes. Subsequent meta-analyses of these led to the recognition of a limited number of intracellular core regulatory processes on which the mutated genes converge [ 51 ]. However, a large fraction of ID and related NDD patients remains undiagnosed after exome-sequencing, opening the possibility of alterations in the non-coding genome.…”

Case report: Phenotype expansion and analysis of TRIO and CNKSR2 variations

“…Many NDDs result in a diffuse and variable presentation of neurological symptoms. Phenotype-based cluster analysis established gene–phenotype relationships and revealed compromised molecular processes in specific NDDs subgroups ( 3 ). For example, patients with pathogenic variations associated with MAPK pathway typically present short stature, ectodermal anomalies, and ID ( 4 ).…”