Rescue strategies for improving defective protein trafficking of the autism-linked mutation R451C in Neuroligin3

Autism Spectrum Disorders (ASDs) are neurodevelopmental syndromes, characterized by behavioral deficits and altered neurotransmission. The etiology of these disorders is complex due to mutations arising in hundreds of genes, along with environmental-derived factors. Among the genetic risk factors, the R451C substitution in the synaptic protein Neuroligin3 (NLGN3) has been highly characterized. It is known from in vitro studies, that the mutation affects folding of the extracellular domain of the protein, causing its retention in the Endoplasmic Reticulum (ER) with only ~10% of the mutant protein reaching the synapse. We have shown that the accumulation of the mutant protein in the ER causes a stress condition and the activation of the UPR in vitro (1) and in a mouse model expressing R451C NLGN3 as the endogenous protein. Specifically, in vivo (2), UPR activation is uniquely detected in the cerebellum and is responsible for the alterations in synaptic neurotransmission that we have detected in this brain area. More recently, we have generated a new cell-based model system allowing us to study the altered trafficking of R451C NLGN3. The result of the screening of an FDA-approved library of compounds identified candidates for improving impaired protein trafficking and correct membrane localization of the mutant protein. The most effective compounds belong to the glucocorticoid family. Collectively, our data show a possible strategy to rescue NLGN3 folding, which could potentially be applied to other protein misfolding disorders.