Division of Organelle Homeostasis, Medical Institute of Bioregulation, Kyushu University, 3-1-1 Maidashi, Fukuoka 812-8582, Japan; Faculty of Arts and Science, Kyushu University, 744 Motooka, Fukuoka 819-0395, Japan.
Division of Organelle Homeostasis, Medical Institute of Bioregulation, Kyushu University, 3-1-1 Maidashi, Fukuoka 812-8582, Japan; Institute of Rheological Functions of Food, Hisayama-machi, Fukuoka 811-2501, Japan.
J Biol Chem. 2020 Apr 17;295(16):5321-5334. doi: 10.1074/jbc.RA119.011989. Epub 2020 Mar 12.
The peroxisome is a subcellular organelle that functions in essential metabolic pathways, including biosynthesis of plasmalogens, fatty acid β-oxidation of very-long-chain fatty acids, and degradation of hydrogen peroxide. Peroxisome biogenesis disorders (PBDs) manifest as severe dysfunction in multiple organs, including the central nervous system (CNS), but the pathogenic mechanisms in PBDs are largely unknown. Because CNS integrity is coordinately established and maintained by neural cell interactions, we here investigated whether cell-cell communication is impaired and responsible for the neurological defects associated with PBDs. Results from a noncontact co-culture system consisting of primary hippocampal neurons with glial cells revealed that a peroxisome-deficient astrocytic cell line secretes increased levels of brain-derived neurotrophic factor (BDNF), resulting in axonal branching of the neurons. Of note, the BDNF expression in astrocytes was not affected by defects in plasmalogen biosynthesis and peroxisomal fatty acid β-oxidation in the astrocytes. Instead, we found that cytosolic reductive states caused by a mislocalized catalase in the peroxisome-deficient cells induce the elevation in BDNF secretion. Our results suggest that peroxisome deficiency dysregulates neuronal axogenesis by causing a cytosolic reductive state in astrocytes. We conclude that astrocytic peroxisomes regulate BDNF expression and thereby support neuronal integrity and function.
过氧化物酶体是一种细胞内细胞器，在重要的代谢途径中发挥作用，包括质体烯的生物合成、极长链脂肪酸的β氧化和过氧化氢的降解。过氧化物酶体生物发生障碍（PBD）表现为多个器官，包括中枢神经系统（CNS）的严重功能障碍，但 PBD 的发病机制在很大程度上尚不清楚。由于中枢神经系统的完整性是通过神经元相互作用协调建立和维持的，我们在这里研究了细胞间通讯是否受损，并负责与 PBD 相关的神经缺陷。由原代海马神经元与神经胶质细胞组成的非接触共培养系统的结果表明，过氧化物酶体缺陷的星形胶质细胞系分泌增加水平的脑源性神经营养因子（BDNF），导致神经元的轴突分支。值得注意的是，星形胶质细胞中的 BDNF 表达不受星形胶质细胞中质体烯生物合成和过氧化物体脂肪酸β氧化缺陷的影响。相反，我们发现过氧化物酶体缺陷细胞中过定位的过氧化氢酶引起的细胞质还原状态导致 BDNF 分泌升高。我们的结果表明，过氧化物酶体缺陷通过在星形胶质细胞中引起细胞质还原状态来扰乱神经元的轴发生。我们得出结论，星形胶质细胞中的过氧化物酶体通过调节 BDNF 的表达来支持神经元的完整性和功能。
