Fatty acid-binding protein 7 triggers α-synuclein oligomerization in glial cells and oligodendrocytes associated with oxidative stress
Fatty acid-binding protein 7 triggers α-synuclein oligomerization in glial cells and oligodendrocytes associated with oxidative stress
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DOI：
10.1038/s41401-021-00675-8
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发表时间：
2021-05-02
影响因子：
8.2
通讯作者：
Fukunaga, Kohji
中科院分区：
文献类型：
--
作者：
Cheng, An;Wang, Yi-Fei;Fukunaga, Kohji
我们先前在帕金森病小鼠模型中发现脂肪酸结合蛋白3(FABP3)触发α-突触核蛋白(Syn)的积聚并诱导多巴胺神经元细胞死亡。但脂肪酸结合蛋白7(FABP7)在大脑中的作用尚不清楚。在这项研究中，我们调查了FABP7是否参与了联体核病。我们发现FABP7与Syn共定位并与Syn形成复合体，花生四烯酸(100M)处理能显著促进FABP7诱导的Syn聚集，这与细胞死亡有关。我们证明了合成的FABP7配体6对FABP7有很高的亲和力，在8-苯胺基-1-磺酸(ANS)实验中K-d值为209 nM；配体6通过破坏FABP7-Syn相互作用提高了U251细胞的存活率。我们发现，在KG-1C人少突胶质细胞和少突胶质前体细胞(OPC)中，心磷脂(10M)激活磷脂酶A2(PLA2)引发内源性Syn和FABP7的寡聚化，并诱导细胞死亡。FABP7配体6(1M)显着减少Syn寡聚和聚集，从而阻止KG-1C和OPC细胞死亡。本研究证明FABP7通过氧化应激触发α-突触核蛋白寡聚，而FABP7配体6可抑制FABP7诱导的Syn寡聚和聚集，从而使胶质细胞和少突胶质细胞免于细胞死亡。
We previously show that fatty acid-binding protein 3 (FABP3) triggers alpha-synuclein (Syn) accumulation and induces dopamine neuronal cell death in Parkinson disease mouse model. But the role of fatty acid-binding protein 7 (FABP7) in the brain remains unclear. In this study we investigated whether FABP7 was involved in synucleinopathies. We showed that FABP7 was co-localized and formed a complex with Syn in Syn-transfected U251 human glioblastoma cells, and treatment with arachidonic acid (100 M) significantly promoted FABP7-induced Syn aggregation, which was associated with cell death. We demonstrated that synthetic FABP7 ligand 6 displayed a high affinity against FABP7 with K-d value of 209 nM assessed in 8-anilinonaphthalene-1-sulfonic acid (ANS) assay; ligand 6 improved U251 cell survival via disrupting the FABP7-Syn interaction. We showed that activation of phospholipase A2 (PLA2) by psychosine (10 M) triggered oligomerization of endogenous Syn and FABP7, and induced cell death in both KG-1C human oligodendroglia cells and oligodendrocyte precursor cells (OPCs). FABP7 ligand 6 (1 M) significantly decreased Syn oligomerization and aggregation thereby prevented KG-1C and OPC cell death. This study demonstrates that FABP7 triggers alpha-synuclein oligomerization through oxidative stress, while FABP7 ligand 6 can inhibit FABP7-induced Syn oligomerization and aggregation, thereby rescuing glial cells and oligodendrocytes from cell death.