Rho GTPases in Intellectual Disability: From Genetics to Therapeutic Opportunities

International Journal of Molecular Sciences

Alessandra Ammoni¹  Emilio Hirsch¹  Valentina Zamboni¹  GiorgioR. Merlo¹  Alessandro Umbach¹  Rebecca Jones¹  Maria Passafaro² 

[1] Department Molecular Biotechnology and Health Science, University of Torino, Via Nizza 52, 10126 Turin, Italy;National Research Council (CNR) Institute for Neuroscience, Via Luigi Vanvitelli, 32, I-20129 Milan, Italy;

关键词: RhoA;    Rac1;    cdc42;    intellectual disability;    neuronal networks;    GTPase pathway;   

DOI  :  10.3390/ijms19061821

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown