Several synaptic proteins have been associated with risk for the mental illnesses schizophrenia and bipolar disorder, suggesting that altered synaptic function may contribute to risk for these diseases. Sequencing of the exomes of unaffected, control subjects and patients with schizophrenia and bipolar disorder has identified a set of rare variants in a synapse specific gene that encodes the Synaptic Guanosine Triphosphatase (GTPase) Activating Protein, or SYNGAP. SYNGAP is a GTPase activating protein (GAP) that, via the ERK signaling pathway, regulates the trafficking of glutamate receptors at synapses. SYNGAP regulates ERK signaling through its interactions with a small GTPase called Ras. Ras promotes the increase in excitatory glutamate receptors at synapses, thus SYNGAP acts as a negative regulator of synaptic excitation. To begin to understand how these and other rare variants may affect SYNGAP function, we have developed several biochemical and cellular assays to delineate how these variants affect SYNGAP expression, SYNGAP regulation of ERK signaling, and biochemical interactions of SYNGAP with other synaptic proteins. Preliminary results show that these variants alter SYNGAP stability. Additionally, our biochemical assays show that SYNGAP variants alter Ras and phospho-ERK signaling, to varying degrees. These experiments will help our group further understand what biochemical pathways may be altered at synapses in schizophrenia and potentially other illnesses, and may help us develop assays to use for novel therapeutic development.
PROJECT: Functionalization of rare variants in SYNGAP, a synaptic protein implicated in schizophrenia
The Broad is an incredible place that is unlike any other research institution. The brilliant minds working here, combined with the level of support and collaboration, leads to unparalleled, world-class research. Everyone here performs cutting-edge research and encourages you through the experimental “failures” so you can accomplish what was previously thought to be impossible. My experience at the Broad has helped me not just become a better scientist and researcher, but also become a better person and collaborator.