Evidences for an evolutionary conserved druggable pathway damaged in models for ARX polyalanine expansions linked to Refractory Epilepsy and Intellectual Disability.

The X-linked ARX gene encodes the Aristaless-related homeobox protein, ARX, an interneuron-specific transcription factor (TF) with a key role in GABAergic interneuron migration and maturation. Expansions of the first two polyalanine tracts (PA1 and PA2) cause refractory epilepsy (RE) with infantile spasms or X-linked Intellectual Disability (XLID). Here we report on an evolutionary conserved druggable ARX-dependent pathway damaged by the faulty functioning of the polyalanine elongated TFs, exerted through a poorly-understood pathogenic mechanism. We have combined the molecular validation of the conserved interaction of ARX with KDM5C from mammals to C.elegans with the analysis of relative neuronal outcomes in order to explore potential compounds able to correct molecular faults behind the ARX polyalanine dysfunction.