Mutations in synaptic cell adhesions molecules and autism spectrum disorders
Synapse formation during nervous system development is a highly ordered process culminating with the recruitment of pre- and post-synaptic proteins to form specialized sites of cell-cell contacts. Multiple cell adhesion complexes operate in parallel to ensure proper synaptic alignment. Several studies have indicated that mutations in synaptic proteins play an important role in the etiology of neurodevelopmental disorders.Mutations affecting function, amounts, folding and trafficking of synaptic proteins may contribute to an imbalance in the excitatory/inhibitory network, leading to impaired neuronal signaling and neurotransmission. In particular genetic alterations in the synaptic cell adhesion molecules neuroligins (NLGNs),neurexins (NRXNs)andcontactin-associated protein2 (CASPR2) genes have been reported in association with autism spectrum disorders (ASDs) and schizophrenia. The R451C NLGN3 was the first mutation to be found in two autistic brothers. This substitutionhasbeenshowntocausesubstantialretentionofNLGN3intheendoplasmicreticulum(ER)inseveralcellularmodelsystems,duetoalocalperturbationintheproteinstructure.The mutation slows down protein processing in the HEK-293 cell line and trafficking in neurons and activates the quality control system by blocking the protein from exiting the ER. In theknock-inmiceforNLGN3R451C, proteindestabilizationinducedbythemutationresultsinonly10%ofmutantprotein.Interestingly,themiceshowagainoffunctionphenotype,characterizedbyalterationsinsynaptictransmissionandbehavioralphenotypesresemblingsomeoftheautisticsymptoms, notobservedintheNLGN3knock-outmice. RetentionofmisfoldedproteinsintheERcanactivateacellularresponse,termedERstress,describedinseveralbraindiseasesbutneverinvestigatedinassociation with ASDs.Ourwork is focused on studying whether mutations in synaptic adhesion proteins, such as theR451Cmutation in NLGN3,activateanERstressresponseinover-expressionstudiesindifferentcellularmodelsystems. This wouldindicateagainoffunctionphenotype at the cellular level,elicitedbythemutantincomparisontothewildtypeprotein.