The main focus of my lab is to elucidate the molecular mechanism(s) leading to synaptic dysfunction and synaptic pruning in various neurodegenerative diseases, such as Alzheimer’s and Huntington disease. Our research has implicated the Rho-family GTPases, RhoA and Rac1, as key players in these synaptopathies. RhoA and Rac1 play critical roles in regulating synapse morphology and dynamics by regulating the actin cytoskeleton. RhoA and Rac1 have antagonistic effects: Rac1 favors the formation and stabilization of new spines, whereas RhoA inhibits their sprouting and promotes their destabilization. This implies that an imbalance in RhoA/Rac1 signaling may have deleterious effects on dendritic maintenance.
Using a combination of genetics, systems biology, molecular biology, and animal models (mouse and drosophila) we have identified several signaling pathways and molecules leading to this imbalance in neurons and glial cells, including APP, Caspase-2, EphA1, and Ube3A. We are actively developing novel tools and models to validate their involvement and to investigate their potential as therapeutic targets.