Physicochemical characterization of the G51D mutation of α-synuclein that is responsible for its severe cytotoxicity
Physicochemical characterization of the G51D mutation of α-synuclein that is responsible for its severe cytotoxicity
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α-突触核蛋白 G51D 突变的理化特征，该突变导致其严重的细胞毒性
DOI：
10.1016/j.neulet.2021.136077
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发表时间：
2021
影响因子：
2.5
通讯作者：
Utsunomiya-Tate Naoko
中科院分区：
文献类型：
--
作者：
Murata Takuya;Tochio Naoya;Utsunomiya-Tate Naoko
原纤维的形成和α-突触核蛋白的聚集对于包括帕金森病在内的神经退行性疾病的发病机制是重要的。在家族性帕金森病中，α-突触核蛋白的G51 D突变导致严重症状和快速进展。α-突触核蛋白是一种本质上无序的蛋白质，具有α-螺旋四聚体结构，可抵抗纤维化和聚集。在这里，我们分离了重组野生型（WT）α-突触核蛋白和G51 D α-突触核蛋白蛋白的稳定二聚体状态。利用圆二色性光谱，我们确定α-突触核蛋白的二聚体和单体结构是未折叠的。WT α-突触核蛋白二聚体比单体更能抵抗原纤维形成。然而，G51 D α-突触核蛋白二聚体的原纤维形成速率与G51 D α-突触核蛋白单体的原纤维形成速率相似。G51 D α-突触核蛋白单体的纤维形态和性质与WT α-突触核蛋白单体和二聚体以及G51 D α-突触核蛋白二聚体的纤维形态和性质不同。此外，G51 D α-突触核蛋白单体原纤维比其他原纤维更具细胞毒性。我们的研究结果表明，G51 D α-突触核蛋白单体原纤维和其他原纤维之间的结构差异是其在家族性帕金森病中严重神经毒性的关键原因。
Fibril formation and aggregation of α-synuclein are important for the pathogenesis of neurodegenerative disorders including Parkinson’s disease. In familial Parkinson’s disease, the G51D mutation of α-synuclein causes severe symptoms and rapid progression. α-Synuclein, an intrinsically disordered protein, was shown to adopt an α-helical tetrameric state that resists fibrillation and aggregation. Here, we isolated the stable dimeric state of recombinant wild-type (WT) α-synuclein and G51D α-synuclein protein. Using circular dichroism spectroscopy, we determined that the α-synuclein dimer and monomer structures were unfolded. The WT α-synuclein dimer was more resistant to fibril formation than the monomer. However, the fibril formation rate of the G51D α-synuclein dimer was similar to that of the G51D α-synuclein monomer. The fibril morphology and properties of the G51D α-synuclein monomer were different from those of the WT α-synuclein monomer and dimer and G51D α-synuclein dimer. Additionally, G51D α-synuclein monomer fibrils were more cytotoxic than other fibrils. Our findings indicate that the structural differences between G51D α-synuclein monomer fibrils and other fibrils are critically responsible for its severe neurotoxicity in familial Parkinson’s disease.
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DOI：
10.1016/j.bbrc.2018.11.200
发表时间：
2019-01
影响因子：
3.1
作者：
G. Tanaka;T. Yamanaka;Y. Furukawa;N. Kajimura;K. Mitsuoka;N. Nukina
通讯作者：
G. Tanaka;T. Yamanaka;Y. Furukawa;N. Kajimura;K. Mitsuoka;N. Nukina
影响因子：
3.5
作者：
Fares, Mohamed-Bilal;Ait-Bouziad, Nadine;Lashuel, Hilal A.
通讯作者：
Lashuel, Hilal A.
影响因子：
2.9
作者：
Weinreb, PH;Zhen, WG;Lansbury, PT
通讯作者：
Lansbury, PT
与双胞胎不同：两种具有不同毒性的α-突触核蛋白多晶型物的NMR比较。
影响因子：
3.7
作者：
Gath J;Bousset L;Habenstein B;Melki R;Böckmann A;Meier BH
通讯作者：
Meier BH
影响因子：
4.8
作者：
Hashimoto, M;Takeda, A;Masliah, E
通讯作者：
Masliah, E