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.

Keywords: GTPase pathway; Rac1; RhoA; cdc42; intellectual disability; neuronal networks.

Figure 1

Regulations of Rho GTPases at the growth cone, by GTPase-activating proteins (GAPs) and Guanine nucleotide Exchange Factors (GEFs) implicated in Intellectual Disability. Green and red boxes surround GEF and GAP proteins, respectively. Asterisks indicate that are mutated in Intellectual Disability (ID) and other human diseases comprising ID. Circled P indicates phosphorylation. Arrows indicate activation, T bars indicate inhibition. A representative small magnification image of a growth cone is provided in the inset (top left). ROCK, Rho kinase-LIM domain kinase; MLC, myosin light chain; PAK1-2-3, p21-activated kinase 1-2-3; LIMK1-2, Rho kinase-LIM domain kinase 1-2.

Figure 2

Regulations of Rho GTPases at the leading edge of a migrating neuron, by GAPs and GEFs implicated in Intellectual Disability. Green and red boxes surround GEF and GAP proteins, respectively. Circled P indicates phosphorylation. Arrows indicate activation, T bars indicate inhibition. A representative small magnification image of a migrating neuron with an evident leading edge is provided in the inset (top left). ROCK, Rho kinase-LIM domain kinase; MLC, myosin light chain; PAK1-2-3, p21-activated kinase 1-2-3; LIMK1-2, Rho kinase-LIM domain kinase 1-2.

Figure 3

Regulations of Rho GTPases at the dendritic spine of an excitatory synapse, by GAPs and GEFs implicated in Intellectual Disability. Green and red boxes surround GEF and GAP proteins, respectively. Asterisks indicate genes that are mutated in ID and other human diseases comprising ID. Circled P indicates phosphorylation. Arrows indicate activation, T bars indicate inhibition. A representative small magnification image of a dendritic spine is provided in the inset (top left). ROCK, Rho kinase-LIM domain kinase; RICS, Rho GTPase activating protein 32; DOCK10, dedicator of cytokinesis 10; RICH2, Rho GTPase activating protein 44; PAK1-2-3, p21-activated kinase 1-2-3; LIMK1-2, Rho kinase-LIM domain kinase 1-2.