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.Bin/amphiphysin/Rvs（BAR）结构域蛋白FAM92A1是一种多功能蛋白，参与调控线粒体超微结构与纤毛发生。然而，FAM92A1在大脑中的生理功能，尤其是在具有特化膜结构的神经元中的功能，仍未得到阐明。本研究证实，在小鼠胚胎发育早期，FAM92A1在大脑及神经元中呈高表达。FAM92A1敲除小鼠可出现大脑形态异常、年龄相关性记忆衰退以及认知功能缺陷。此外，FAM92A1的缺失会诱发海马神经元变性，并破坏神经元复杂性与突触可塑性。尤为关键的是，FAM92A1缺乏会引发膜重塑异常，并干扰神经元内吞过程。通过解析FAM92A1的BAR结构域晶体结构，我们揭示了其固有的二聚体形成能力，该能力可形成独特的弯曲构象，对膜重塑发挥关键作用。结合结构生物学与分子模拟实验，我们进一步全面阐明了FAM92A1与膜结合后如何诱导脂质聚集并产生膜曲率。综上，本研究为阐明FAM92A1在大脑中的生理功能提供了重要参考。本研究揭示了FAM92A1通过调控膜重塑与内吞过程，进而调节突触可塑性及神经功能的分子机制。