Sushi domain proteins as synapse protective factors in brain development and aging

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Project Summary/Abstract Synapse formation and elimination are fundamental processes that is essential for the assembly of neural circuits in the brain during development. Defects in these processes result in abnormal synaptic densities in the brain, which is believed to contribute towards the pathogenesis of many neurodevelopmental disorders. The goal of the proposed research is to understand how Sushi Repeat Protein X-linked 2 (SRPX2) regulates synapse density in the brain. We have previously shown that the sushi repeat protein X-linked 2 (SRPX2) gene codes for a neuronally-expressed secreted synaptogenic protein that increases the density of excitatory synapses in cor- tical neurons. Sushi repeats are predominantly found in known complement regulators in the periphery. Our preliminary data suggests that SRPX2 inhibits complement activation in the brain, thereby decreasing synapse pruning and increasing synapse density. To test this hypothesis, we proposed the following aims. Aim 1: Deter- mine if SRPX2 signals through the classical complement pathway to regulate synapse density and elimination. Aim 2: Determine if SRPX2 inhibits the classical complement cascade by binding to C1q. Aim 3: Determine if SRPX2 is required in the adult and aged brain for synapse maintenance. We anticipate that these studies will provide new insights into the molecular mechanisms underlying synapse elimination in the developing brain, and may lead to novel therapeutic approaches for treating developmental and degenerative brain disorders.