Understanding intellectual disability through RASopathies

Abstract

Intellectual disability, commonly known as mental retardation in the International Classification of Disease from World Health Organization, is the term that describes an intellectual and adaptive cognitive disability that begins in early life during the developmental period. Currently the term intellectual disability is the preferred one. Although our understanding of the physiological basis of learning and learning disability is poor, a general idea is that such condition is quite permanent. However, investigations in animal models suggest that learning disability can be functional in nature and as such reversible through pharmacology or appropriate learning paradigms. A fraction of the cases of intellectual disability is caused by point mutations or deletions in genes that encode for proteins of the RAS/MAP kinase signaling pathway known as RASopathies. Here we examined the current understanding of the molecular mechanisms involved in this group of genetic disorders focusing in studies which provide evidence that intellectual disability is potentially treatable and curable. The evidence presented supports the idea that with the appropriate understanding of the molecular mechanisms involved, intellectual disability could be treated pharmacologically and perhaps through specific mechanistic-based teaching strategies.

Keywords: Learning deficit; Learning strategies; Pharmacological treatment; Phenotypic reversion; RAS/MAP kinase signaling pathway.

Figure 1. Schematic representation of Ras/ERK signal transduction pathway

RASopathies are a group of neurodevelopmental disorders with overlaping clinical features and characterized by germline mutations in genes that encodes for proteins involved in this pathway (illustrated in color code). This group includes the following disorders: Noonan syndrome (NS), Noonan syndrome with multiple lentigines (NSML), NF1-Like syndrome (NF1-like), neurofibromatosis type 1 (NF1), capillary malformation–arteriovenous malformation syndrome (CM-AVM), cardio-facio-cutaneous syndrome (CFC), and Costello syndrome (CS). Red asterisk indicates molecular components where functional rescued was achieved.

Figure 2. Activity-dependent ERK activation model and signal carried from spines to the nucleus by ERK

The activation of multiple receptors and complementary pathways are needed. The excitatory neurotransmitter glutamate over spines produces receptor activation, which in turn generates neuron depolarization and Ca2+ influx, through NMDA receptor and VSCC. Ca2+ activates many process, among them, Ca2+/Calmodulin (Ca2+/CaM) complex and RAS activation. Ca2+/CaM together with dopamine activate AC, increasing cAMP levels, which recruits and activates PKA. Activation of RAS, by Ca2+-dependent and growth factor-dependent mechanisms, can activates ERK through MEK1/2 and PKB through PI3K. mGluRs are able to activate PKC through PLC/DAG pathway. All these signaling pathways seem to be important for Erk activity, including nuclear and cytosolic activities (represented by a box) like AMPAR exocytosis regulation and Rsk2 phosphorylation. In the nucleus ERK and other kinases (Rsk2 and CaMKIV) phosphorylate and activate the cAMP response element-binding (CREB).