Shioda Norifumi, Yabuki Yasushi, Kobayashi Yuka, Onozato Misaki, Owada Yuji, Fukunaga Kohji
From the Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai 980-8578 and.
the Department of Organ Anatomy, Graduate School of Medicine, Yamaguchi University, Ube 755-8505, Japan.
J Biol Chem. 2014 Jul 4;289(27):18957-65. doi: 10.1074/jbc.M113.527341. Epub 2014 May 22.
α-Synuclein (αSyn) accumulation in dopaminergic (DA) neurons is partly regulated by long-chain polyunsaturated fatty acids. We found that fatty acid-binding protein 3 (FABP3, H-FABP), a factor critical for arachidonic acid (AA) transport and metabolism in brain, is highly expressed in DA neurons. Fabp3 knock-out (Fabp3(-/-)) mice were resistant to 1-methyl-1,2,3,6-tetrahydropiridine-induced DA neurodegeneration in the substantia nigra pars compacta and showed improved motor function. Interestingly, FABP3 interacted with αSyn in the substantia nigra pars compacta, and αSyn accumulation following 1-methyl-1,2,3,6-tetrahydropiridine treatment was attenuated in Fabp3(-/-) compared with wild-type mice. We confirmed that FABP3 overexpression aggravates AA-induced αSyn oligomerization and promotes cell death in PC12 cells, whereas overexpression of a mutant form of FABP3 lacking fatty-acid binding capacity did not. Taken together, αSyn oligomerization in DA neurons is likely aggravated by AA through FABP3 in Parkinson disease pathology.
α-突触核蛋白（αSyn）在多巴胺能（DA）神经元中的积累部分受长链多不饱和脂肪酸调节。我们发现，脂肪酸结合蛋白3（FABP3，H-FABP），一种对脑中花生四烯酸（AA）转运和代谢至关重要的因子，在DA神经元中高度表达。Fabp3基因敲除（Fabp3(-/-)）小鼠对1-甲基-1,2,3,6-四氢吡啶诱导的黑质致密部DA神经退行性变具有抗性，并表现出运动功能改善。有趣的是，FABP3在黑质致密部与αSyn相互作用，与野生型小鼠相比，Fabp3(-/-)小鼠在1-甲基-1,2,3,6-四氢吡啶处理后αSyn的积累减弱。我们证实，FABP3过表达会加重AA诱导的PC12细胞中αSyn寡聚化并促进细胞死亡，而缺乏脂肪酸结合能力的FABP3突变体形式的过表达则不会。综上所述，在帕金森病病理学中，AA可能通过FABP3加重DA神经元中的αSyn寡聚化。
