Pathophysiological Mechanisms in Neurodevelopmental Disorders Caused by Rac GTPases Dysregulation: What’s behind Neuro-RACopathies

Abstract

Rho family guanosine triphosphatases (GTPases) regulate cellular signaling and cytoskeletal dynamics, playing a pivotal role in cell adhesion, migration, and cell cycle progression. The Rac subfamily of Rho GTPases consists of three highly homologous proteins, Rac 1–3. The proper function of Rac1 and Rac3, and their correct interaction with guanine nucleotide-exchange factors (GEFs) and GTPase-activating proteins (GAPs) are crucial for neural development. Pathogenic variants affecting these delicate biological processes are implicated in different medical conditions in humans, primarily neurodevelopmental disorders (NDDs). In addition to a direct deleterious effect produced by genetic variants in the RAC genes, a dysregulated GTPase activity resulting from an abnormal function of GEFs and GAPs has been involved in the pathogenesis of distinctive emerging conditions. In this study, we reviewed the current pertinent literature on Rac-related disorders with a primary neurological involvement, providing an overview of the current knowledge on the pathophysiological mechanisms involved in the neuro-RACopathies.

Rac1 as a Target to Treat Dysfunctions and Cancer of the Bladder

“…Dysregulations of Rac signaling have been reported in atherosclerosis [ 22 ], neurodevelopmental disorders [ 23 ], rheumatic diseases [ 24 ], pulmonary hypertension [ 25 ] and different types of cancers, including urothelial carcinoma [ 26 , 27 ]. Protein Rac1 (RAS-related C3 botulinum toxin substrate (1) is considered a prime target to combat a variety of solid tumors and certain onco-hematological malignancies.…”

Impaired Function of PLEKHG2, a Rho-Guanine Nucleotide-Exchange Factor, Disrupts Corticogenesis in Neurodevelopmental Phenotypes

“…PLEKHG2 (Pleckstrin homology and RhoGEF domain containing G2), which is a GEF for Rac and Cdc42, interacts with Gβγ subunits of heterotrimeric G proteins and is activated upon co-expression of Gβγ in various cell types; whether activation is mediated directly by Gβγ remains to be clarified [ 8 , 9 , 10 , 11 , 12 ]. Rac and Cdc42 are crucial for the spatiotemporal activation of various effectors to control cell morphology through cytoskeletal organization, and they have been reported to be important for the cortical neuron development [ 13 , 14 , 15 , 16 , 17 , 18 ].…”

ARHGEF9 gene variant leads to developmental and epileptic encephalopathy: Genotypic phenotype analysis and treatment exploration

“…The ARHGEF9 gene (OMIM: 300429) encodes collybistin, which belongs to the Rho‐like GTPases family, which acts as a molecular switch by cycling from an active GTP‐bound state to an inactive GTP‐bound state, playing a pivotal role in the formation of postsynaptic glycine and inhibitory gamma‐aminobutyric acid receptor clusters and is involved in the regulation of neural excitability and the pathogenesis of epilepsy (Scala, Nishikawa, et al, 2021 ; Shimojima et al, 2011 ). ARHGEF9 gene is associated with an X‐linked developmental‐epileptic encephalopathy and extensive clinical phenotype, including hyperactivity; impulsivity, hypotonia, and autism spectrum disorder (Alber et al, 2017 ; Harvey et al, 2004 ).…”