FAM92A1 Regulates Neural Structure and Function through Membrane Remodeling

The Bin/amphiphysin/Rvs (BAR) domain protein FAM92A1 is a multifunctional protein engaged in the regulation of mitochondrial ultrastructure and ciliogenesis. However, the physiological role of FAM92A1 in the brain, particularly in neurons with specialized membrane architecture, remains unexplored. Here, we demonstrate that FAM92A1 is prominently expressed in the brain and neurons during early mouse embryonic development. FAM92A1 knockout mice display brain morphology alterations, age-associated memory decline, and cognitive deficits. Moreover, the absence of FAM92A1 triggers hippocampal neuron degeneration and disrupts neuronal complexity and synaptic plasticity. Crucially, FAM92A1 deficiency leads to anomalies in membrane remodeling and disturbances in neuronal endocytic processes. Through analysis of the crystal structure of the FAM92A1 BAR domain, we unveil its intrinsic capability to form dimers, contributing to a distinctive curved conformation critical for membrane remodeling. By combining structural and molecular simulation, we further gain a comprehensive understanding of how FAM92A1 interacts with membranes to induce lipid clustering and generate membrane curvature. In summary, our study provides valuable insights into the physiological function of FAM92A1 in the brain. It uncovers the molecular mechanisms through which FAM92A1 regulates synaptic plasticity and neural function by influencing membrane remodeling and endocytic processes.