Wang Yifei, Shinoda Yasuharu, Cheng An, Kawahata Ichiro, Fukunaga Kohji
Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3 Aramaki-Aoba, Aoba-ku, Sendai 980-8578, Japan.
Biomedicines. 2021 Jan 22;9(2):110. doi: 10.3390/biomedicines9020110.
The accumulation of α-synuclein (αSyn) has been implicated as a causal factor in the pathogenesis of Parkinson's disease (PD). There is growing evidence that supports mitochondrial dysfunction as a potential primary cause of dopaminergic neuronal death in PD. Here, we focused on reciprocal interactions between αSyn aggregation and mitochondrial injury induced by oxidative stress. We further investigated whether epidermal fatty acid-binding protein 5 (FABP5) is related to αSyn oligomerization/aggregation and subsequent disturbances in mitochondrial function in neuronal cells. In the presence of rotenone, a mitochondrial respiratory chain complex I inhibitor, co-overexpression of FABP5 with αSyn significantly decreased the viability of Neuro-2A cells compared to that of αSyn alone. Under these conditions, FABP5 co-localized with αSyn in the mitochondria, thereby reducing mitochondrial membrane potential. Furthermore, we confirmed that pharmacological inhibition of FABP5 by its ligand prevented αSyn accumulation in mitochondria, which led to cell death rescue. These results suggested that FABP5 is crucial for mitochondrial dysfunction related to αSyn oligomerization/aggregation in the mitochondria induced by oxidative stress in neurons.
α-突触核蛋白（αSyn）的积累被认为是帕金森病（PD）发病机制中的一个致病因素。越来越多的证据支持线粒体功能障碍是PD中多巴胺能神经元死亡的潜在主要原因。在此，我们聚焦于αSyn聚集与氧化应激诱导的线粒体损伤之间的相互作用。我们进一步研究了表皮脂肪酸结合蛋白5（FABP5）是否与神经元细胞中αSyn的寡聚化/聚集以及随后的线粒体功能紊乱有关。在线粒体呼吸链复合体I抑制剂鱼藤酮存在的情况下，与单独表达αSyn相比，FABP5与αSyn共过表达显著降低了Neuro-2A细胞的活力。在这些条件下，FABP5与αSyn在线粒体中共定位，从而降低线粒体膜电位。此外，我们证实其配体对FABP5的药理学抑制可防止αSyn在线粒体中积累，从而挽救细胞死亡。这些结果表明，FABP5对于神经元氧化应激诱导的线粒体中与αSyn寡聚化/聚集相关的线粒体功能障碍至关重要。
