Structure-function characterization of TANC2, a novel postsynaptic candidate associated to neuropsychiatric disorders

This project has been funded thanks to the Joint Call Fondazione Cariplo and Fondazione Telethon 2022

Different neuropsychiatric disorders are associated to mutations of genes encoding proteins that organize synapses in our nervous system. These proteins assemble networks in the presynaptic or postsynaptic terminal to build up a synapse, and are essential for the efficient transmission of electric signals between neurons. If these protein networks are altered by mutation, the activity of the synapses can be affected, leading to disturbed transmission of signals, with consequences that give rise to distinct neuropsychiatric diseases. Our laboratory is interested in the molecular mechanisms to organize a functional synapse. We look for important players in the organization of synaptic terminals. During the analysis of the mechanisms modulating the function of one of these protein networks, we identified the protein TANC2, that is mutated in patients with disorders including autism, schizophrenia and other forms of intellectual disability. There is limited information on TANC2; we propose to investigate the structure-function relationship linking TANC2 to the organization of postsynaptic terminals. Using programs predicting the structural features of proteins, we found that TANC2 contains flexible disordered protein regions. We plan to confirm experimentally the presence of disordered regions, and to compare their structure with structures obtained by specific mutations in TANC2 gene of neuropsychiatric patients. We will introduce wildtype or mutated proteins into neurons to study their effects on synaptic organization. Results from this study are expected to clarify important aspects of TANC2 structure relevant to its function, and to identify synaptic defects that may contribute to the development of the associated neuropsychiatric disorders.