Graduate Student Yale University New Haven , Connecticut, United States
Ellen Corcoran (Yale University)| Josie Bircher (Yale University)| Anthony Koleske (Yale University)
There is a critical need to elucidate the biochemical events that control dendrite and synapse function to develop better targeted therapeutic strategies for neurodevelopmental disorders. Functionally damaging mutations in the TRIO gene are enriched in individuals with neurodevelopmental disorders. TRIO encodes a large synaptic regulatory protein with three catalytic domains and several accessory domains, including nine spectrin repeat domains. De novo missense mutations and rare damaging variants in the spectrin repeats are enriched in autism, intellectual disability, and developmental delay. However, the role of TRIO’s spectrin repeats and the impact of disease-associated mutations remains completely unknown. Our goals are to identify spectrin repeat binding partners, explore the possibility of spectrin repeats intramolecularly regulating TRIO catalytic activity, and determine the impact of disease mutations on spectrin repeat function. In doing so, we will elucidate how TRIO’s spectrin repeats confer proper neuronal development and determine whether and how TRIO disease-associated variants compromise signaling mechanisms.