Dissertation Defense: Jeremiah Paskus
Candidate Name: Jeremiah D. Paskus, M.A.
Advisors: Katherine Roche, Ph.D. and Jeffrey Huang, Ph.D.
Title: Synaptic Kalirin-7 and Trio Interactomes Reveal a GEF Protein-Dependent Neuroligin-1 Mechanism of Action
The RhoGEFs Kalirin and Trio have emerged as significant regulators of synaptic plasticity, and their dysregulation has recently been associated across a range of neurodevelopmental and neurodegenerative disorders. Although studies have implicated both Kalirin and Trio in certain diseases, such as tauopathies, they remarkably differ in their association with other neurological disorders, namely Autism Spectrum Disorders. We used unbiased proteomic analysis to identify the interactomes of Kalirin-7 and Trio to ascertain distinct protein interaction networks associated with their respective function in synaptic transmission and disease, and revealed groups of proteins that preferentially interact with a particular RhoGEF. We find Trio interacts with a range of axon guidance, presynaptic, and disease associated complexes, whereas Kalirin-7 strongly associates with synaptic adhesion molecules. Specifically, we show Kalirin-7 is a preferential interactor of the cell adhesion molecule Neuroligin-1 (NLGN1). To determine the functional significance of this interaction, we performed a combination of biochemical, imaging, and electrophysiological experiments showing that NLGN1-dependent synaptic function is mediated through Kalirin-7 in an interaction-dependent manner. Thus, our data reveal not only the first interactomes of two important disease related proteins, but also provides the first downstream intracellular effector of NLGN1 function.
Friday, December 13, 2019 at 1:30pm to 3:30pm
Medical and Dental Building, Proctor Harvey Amphitheater
3900 Reservoir Road, N.W., Washington