By Leonard Kaczmarek

Fragile X Syndrome (FXS) patients exhibit several neurological symptoms including intellectual disability, repetitive behaviors and transient childhood seizures. It is caused by loss of expression of FMRP, a polyribosome-associated neuronal RNA-binding protein implicated in regulation of mRNA translation.

A canonical role of FMRP is to repress the synthesis of its mRNA targets, leading to excessive protein synthesis. It the past several years, however, it has been discovered that FMRP also directly binds several ion channels that regulate the frequency and timing of neuron action potentials. One of these channels is Slack (also termed KCNT1).

Human mutations in Slack also produce very severe intellectual disability and early onset seizures. Recent work has found that activation of Slack stimulates the translation of mRNAs in neurons and that mutations in Slack produce excess unregulated translation -- as does the loss of FMRP. Surprisingly, FMRP suppresses the ability of Slack to stimulate translation, providing an additional and previously uncharacterized mechanism for how FMRP regulates protein synthesis.

We therefore plan to test two newly discovered pharmacological inhibitors of Slack channels on behaviors in a mouse model of Fragile X syndrome and on mRNA translation. This study may provide a novel therapeutic avenue for the treatment of Fragile X syndrome patients.