Rho GTPases in Intellectual Disability: From Genetics to Therapeutic Opportunities

Abstract

Rho-class small GTPases are implicated in basic cellular processes at nearly all brain developmental steps, from neurogenesis and migration to axon guidance and synaptic plasticity. GTPases are key signal transducing enzymes that link extracellular cues to the neuronal responses required for the construction of neuronal networks, as well as for synaptic function and plasticity. Rho GTPases are highly regulated by a complex set of activating (GEFs) and inactivating (GAPs) partners, via protein:protein interactions (PPI). Misregulated RhoA, Rac1/Rac3 and cdc42 activity has been linked with intellectual disability (ID) and other neurodevelopmental conditions that comprise ID. All genetic evidences indicate that in these disorders the RhoA pathway is hyperactive while the Rac1 and cdc42 pathways are consistently hypoactive. Adopting cultured neurons for in vitro testing and specific animal models of ID for in vivo examination, the endophenotypes associated with these conditions are emerging and include altered neuronal networking, unbalanced excitation/inhibition and altered synaptic activity and plasticity. As we approach a clearer definition of these phenotype(s) and the role of hyper- and hypo-active GTPases in the construction of neuronal networks, there is an increasing possibility that selective inhibitors and activators might be designed via PPI, or identified by screening, that counteract the misregulation of small GTPases and result in alleviation of the cognitive condition. Here we review all knowledge in support of this possibility.

The intellectual disability protein Oligophrenin‐1 controls astrocyte morphology and migration

“…The dysregulation of those proteins is widely implicated in ID. It was indeed reported that in most pathological cases, RhoA is hyperactivated (Ramakers et al, 2012;Zamboni et al, 2018), although some cases of ID rather show a hypo-activation of the RhoA/ROCK/MLC2 pathway (Kutsche et al, 2000;Ravindran et al, 2017). These data indicate that this pathway, when unbalanced, leads to a pathological state.…”

“…Several identified genes implicated in XLID are involved in the regulation of the RhoGTPases (Ba, van der Raadt, & Nadif Kasri, 2013;Zamboni et al, 2018), which are small GTPase proteins of the Rho family that play a critical role in cytoskeleton remodeling. They regulate different cellular processes such as migration, adhesion and morphology (Etienne-Manneville & Hall, 2002;Raftopoulou & Hall, 2004;Ridley, 2001).…”

Non‐syndromic X linked intellectual disability: Current knowledge in light of the recent advances in molecular and functional studies

“…GRIA3 (OMIM *305915), on the other hand, is part of the α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazole acid (AMPA) glutamate receptor. These scaffolding proteins are the core of the synapse because they translate upstream signals from CAM and receptors to changes in gene expression or cytoskeleton organization …”

Synaptic actin stabilization protein loss in Down syndrome and Alzheimer disease

“…Disruption of PAK‐Arp2/3 function leads to defective synaptic plasticity and learning deficits in association with intellectual disability . Other studies show that PAK3 gene mutations, that disrupt kinase activation or function, cause X‐linked intellectual disability . Reduced regional PAK levels are described for AD brains , and decreased PAK expression in a triple transgenic AD mouse model has been associated with dendrite and spine defects .…”