An α-synuclein decoy peptide prevents cytotoxic α-synuclein aggregation caused by fatty acid binding protein 3.
An α-synuclein decoy peptide prevents cytotoxic α-synuclein aggregation caused by fatty acid binding protein 3.
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DOI：
10.1016/j.jbc.2021.100663
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发表时间：
2021-01
期刊：
影响因子：
--
通讯作者：
Kawata Y
中科院分区：
文献类型：
--
作者：
Fukui N;Yamamoto H;Miyabe M;Aoyama Y;Hongo K;Mizobata T;Kawahata I;Yabuki Y;Shinoda Y;Fukunaga K;Kawata Y
α-突触核蛋白（αSyn）是一种已知在帕金森病表现期间形成细胞内聚集体的蛋白质。此前，研究表明，在不具有编码脂质转运蛋白脂肪酸结合蛋白3（FABP 3）的基因的小鼠中脑区域，αSyn聚集受到强烈抑制。在体外实验中发现这两种蛋白之间存在相互作用，提示FABP 3可能在αSyn在神经元内的聚集和沉积中发挥作用。为了表征FABP 3和αSyn之间相互作用的分子机制，调节后者的细胞积累，在本报告中，我们使用体外荧光测定结合荧光显微镜，透射电子显微镜和石英晶体微天平测定来详细表征FABP 3-αSyn相互作用的过程和结果。我们证明了FABP 3与αSyn的结合导致后者聚集机制的变化;具体而言，抑制了αSyn的纤维形式，并且还产生了对小鼠neuro 2A细胞具有增强细胞毒性的聚集体。由于这种相互作用涉及αSyn的C-末端序列区域，因此我们测试了源自αSyn该区域的肽（α SynP 130 -140）作为诱饵，以阻止FABP 3-αSyn相互作用。我们观察到该肽在体外和培养的细胞中竞争性抑制αSyn与FABP 3的结合。我们认为α SynP 130 -140的给药可能用于防止细胞中毒性FABP 3-αSyn寡聚体的积累，从而防止帕金森病的进展。
α-synuclein (αSyn) is a protein known to form intracellular aggregates during the manifestation of Parkinson’s disease. Previously, it was shown that αSyn aggregation was strongly suppressed in the midbrain region of mice that did not possess the gene encoding the lipid transport protein fatty acid binding protein 3 (FABP3). An interaction between these two proteins was detected in vitro, suggesting that FABP3 may play a role in the aggregation and deposition of αSyn in neurons. To characterize the molecular mechanisms that underlie the interactions between FABP3 and αSyn that modulate the cellular accumulation of the latter, in this report, we used in vitro fluorescence assays combined with fluorescence microscopy, transmission electron microscopy, and quartz crystal microbalance assays to characterize in detail the process and consequences of FABP3–αSyn interaction. We demonstrated that binding of FABP3 to αSyn results in changes in the aggregation mechanism of the latter; specifically, a suppression of fibrillar forms of αSyn and also the production of aggregates with an enhanced cytotoxicity toward mice neuro2A cells. Because this interaction involved the C-terminal sequence region of αSyn, we tested a peptide derived from this region of αSyn (αSynP130-140) as a decoy to prevent the FABP3–αSyn interaction. We observed that the peptide competitively inhibited binding of αSyn to FABP3 in vitro and in cultured cells. We propose that administration of αSynP130-140 might be used to prevent the accumulation of toxic FABP3-αSyn oligomers in cells, thereby preventing the progression of Parkinson’s disease.
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影响因子：
2.8
作者：
Owada, Y;Yoshimoto, T;Kondo, H
通讯作者：
Kondo, H
影响因子：
2.5
作者：
Hirose M;Sugiyama S;Ishida H;Niiyama M;Matsuoka D;Hara T;Mizohata E;Murakami S;Inoue T;Matsuoka S;Murata M
通讯作者：
Murata M
影响因子：
4.7
作者：
Kawahata I;Sekimori T;Wang H;Wang Y;Sasaoka T;Bousset L;Melki R;Mizobata T;Kawata Y;Fukunaga K
通讯作者：
Fukunaga K
影响因子：
16.6
作者：
Matsuoka, Shigeru;Sugiyama, Shigeru;Matsuoka, Daisuke;Hirose, Mika;Lethu, Sebastien;Ano, Hikaru;Hara, Toshiaki;Ichihara, Osamu;Kimura, S. Roy;Murakami, Satoshi;Ishida, Hanako;Mizohata, Eiichi;Inoue, Tsuyoshi;Murata, Michio
通讯作者：
Murata, Michio
影响因子：
14.9
作者：
Micsonai A;Wien F;Bulyáki É;Kun J;Moussong É;Lee YH;Goto Y;Réfrégiers M;Kardos J
通讯作者：
Kardos J