Yin Jun, Chen Hsueh-Ling, Grigsby-Brown Anna, He Yi, Cotten Myriam L, Short Jacob, Dermady Aidan, Lei Jingce, Gibbs Mary, Cheng Ethan S, Zhang Dean, Long Caixia, Xu Lele, Zhong Tiffany, Abzalimov Rinat, Haider Mariam, Sun Rong, He Ye, Zhou Qiangjun, Tjandra Nico, Yuan Quan
Dendrite Morphogenesis and Plasticity Unit, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD.
Fermentation Facility, Biochemistry and Biophysics Center, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD.
bioRxiv. 2024 Apr 11:2024.04.10.588417. doi: 10.1101/2024.04.10.588417.
Glia derived secretory factors play diverse roles in supporting the development, physiology, and stress responses of the central nervous system (CNS). Through transcriptomics and imaging analyses, we have identified Obp44a as one of the most abundantly produced secretory proteins from CNS glia. Protein structure homology modeling and Nuclear Magnetic Resonance (NMR) experiments reveal Obp44a as a fatty acid binding protein (FABP) with a high affinity towards long-chain fatty acids in both native and oxidized forms. Further analyses demonstrate that Obp44a effectively infiltrates the neuropil, traffics between neuron and glia, and is secreted into hemolymph, acting as a lipid chaperone and scavenger to regulate lipid and redox homeostasis in the developing brain. In agreement with this essential role, deficiency of Obp44a leads to anatomical and behavioral deficits in adult animals and elevated oxidized lipid levels. Collectively, our findings unveil the crucial involvement of a noncanonical lipid chaperone to shuttle fatty acids within and outside the brain, as needed to maintain a healthy brain lipid environment. These findings could inspire the design of novel approaches to restore lipid homeostasis that is dysregulated in CNS diseases.
神经胶质细胞衍生的分泌因子在支持中枢神经系统（CNS）的发育、生理功能和应激反应中发挥着多种作用。通过转录组学和成像分析，我们已确定Obp44a是中枢神经系统神经胶质细胞产生的分泌蛋白中产量最高的蛋白之一。蛋白质结构同源性建模和核磁共振（NMR）实验表明，Obp44a是一种脂肪酸结合蛋白（FABP），对天然形式和氧化形式的长链脂肪酸均具有高亲和力。进一步分析表明，Obp44a能有效渗透到神经毡中，在神经元和神经胶质细胞之间运输，并分泌到血淋巴中，作为脂质伴侣和清除剂来调节发育中大脑的脂质和氧化还原稳态。与这一重要作用一致，Obp44a的缺乏会导致成年动物出现解剖学和行为缺陷以及氧化脂质水平升高。总的来说，我们的研究结果揭示了一种非典型脂质伴侣在根据需要在脑内外穿梭脂肪酸以维持健康的脑脂质环境方面的关键作用。这些发现可能会激发设计新方法来恢复在中枢神经系统疾病中失调的脂质稳态。
