Mental Health Center and National Chengdu Center for Safety Evaluation of Drugs, State Key Laboratory of Biotherapy, West China Hospital of Sichuan University, Chengdu, 610041, China.
Faculty of Biological and Environmental Sciences, University of Helsinki, 00014, Helsinki, Finland.
Nat Commun. 2024 Jul 23;15(1):6209. doi: 10.1038/s41467-024-50565-w.
The Bin/Amphiphysin/Rvs (BAR) domain protein FAM92A1 is a multifunctional protein engaged in regulating mitochondrial ultrastructure and ciliogenesis, but its physiological role in the brain remains unclear. Here, we show that FAM92A1 is expressed in neurons starting from embryonic development. FAM92A1 knockout in mice results in altered brain morphology and age-associated cognitive deficits, potentially due to neuronal degeneration and disrupted synaptic plasticity. Specifically, FAM92A1 deficiency impairs diverse neuronal membrane morphology, including the mitochondrial inner membrane, myelin sheath, and synapses, indicating its roles in membrane remodeling and maintenance. By determining the crystal structure of the FAM92A1 BAR domain, combined with atomistic molecular dynamics simulations, we uncover that FAM92A1 interacts with phosphoinositide- and cardiolipin-containing membranes to induce lipid-clustering and membrane curvature. Altogether, these findings reveal the physiological role of FAM92A1 in the brain, highlighting its impact on synaptic plasticity and neural function through the regulation of membrane remodeling and endocytic processes.
Bin/Amphiphysin/Rvs (BAR) 结构域蛋白 FAM92A1 是一种多功能蛋白，参与调节线粒体超微结构和纤毛发生，但它在大脑中的生理作用尚不清楚。在这里，我们表明 FAM92A1 从胚胎发育开始就在神经元中表达。FAM92A1 敲除小鼠导致大脑形态改变和年龄相关的认知缺陷，这可能是由于神经元变性和突触可塑性受损所致。具体来说，FAM92A1 缺乏会损害多种神经元膜形态，包括线粒体内膜、髓鞘和突触，表明其在膜重塑和维持中的作用。通过确定 FAM92A1 BAR 结构域的晶体结构，并结合原子分子动力学模拟，我们揭示 FAM92A1 与含有磷酸肌醇和心磷脂的膜相互作用，诱导脂质聚集和膜曲率。总之，这些发现揭示了 FAM92A1 在大脑中的生理作用，强调了其通过调节膜重塑和内吞过程对突触可塑性和神经功能的影响。
