The α-Synuclein Monomer May Have Different Misfolding Mechanisms in the Induction of α-Synuclein Fibrils with Different Polymorphs.
The α-Synuclein Monomer May Have Different Misfolding Mechanisms in the Induction of α-Synuclein Fibrils with Different Polymorphs.
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DOI：
10.3390/biom13040682
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发表时间：
2023-04-17
期刊：
影响因子：
5.5
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中科院分区：
文献类型：
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α-突触核蛋白（α-Syn）的聚集与帕金森病等神经退行性疾病的发生密切相关。α-Syn单体的错误折叠在聚集体的形成和纤维的延伸中起着关键作用。然而，α-Syn的错误折叠机制仍然是难以捉摸的。在此，选择了三种不同的α-Syn原纤维（从患病人脑中分离，通过体外辅因子-tau诱导产生，以及通过体外无辅因子诱导获得）用于研究。基于常规分子动力学（MD）和Steered MD模拟方法，通过研究α-Syn的边界链解离，揭示了其错误折叠的机制.结果表明，三种体系中边界链的解离途径不同。根据解离的逆过程，我们得出结论，在人脑系统中，单体和模板的结合从C-末端开始，并逐渐向N-末端错折叠。在辅因子-tau系统中，单体结合从残基58-66（含有β3）开始，随后是C-末端卷曲（残基67-79）。然后，N-末端螺旋（残基36-41）和残基50-57（含有β2）与模板结合，然后是残基42-49（含有β1）。在无辅因子体系中，发现了两条错误折叠路径，一条是单体先与N/C端（β1/β6）结合，再与剩余残基结合;另一个是单体从C端到N端顺序结合，类似于人脑系统。此外，在人脑和辅因子-tau系统中，静电相互作用（特别是来自残基58-66）是错误折叠过程期间的主要驱动力，而在无辅因子系统中，静电和货车范德华相互作用的贡献是相当的。这些结果为深入理解α-Syn的错误折叠和聚集机制提供了理论依据。
The aggregation of alpha-synuclein (α-Syn) is closely related to the occurrence of some neurodegenerative diseases such as Parkinson’s disease. The misfolding of α-Syn monomer plays a key role in the formation of aggregates and extension of fibril. However, the misfolding mechanism of α-Syn remains elusive. Here, three different α-Syn fibrils (isolated from a diseased human brain, generated by in vitro cofactor-tau induction, and obtained by in vitro cofactor-free induction) were selected for the study. The misfolding mechanisms of α-Syn were uncovered by studying the dissociation of the boundary chains based on the conventional molecular dynamics (MD) and Steered MD simulations. The results showed that the dissociation paths of the boundary chains in the three systems were different. According to the reverse process of dissociation, we concluded that in the human brain system, the binding of the monomer and template starts from the C-terminal and gradually misfolds toward the N-terminal. In the cofactor-tau system, the monomer binding starts from residues 58–66 (contain β3), followed by the C-terminal coil (residues 67–79). Then, the N-terminal coil (residues 36–41) and residues 50–57 (contain β2) bind to the template, followed by residues 42–49 (contain β1). In the cofactor-free system, two misfolding paths were found. One is that the monomer binds to the N/C-terminal (β1/β6) and then binds to the remaining residues. The other one is that the monomer binds sequentially from the C- to N-terminal, similar to the human brain system. Furthermore, in the human brain and cofactor-tau systems, electrostatic interactions (especially from residues 58–66) are the main driving force during the misfolding process, whereas in the cofactor-free system, the contributions of electrostatic and van der Waals interactions are comparable. These results may provide a deeper understanding for the misfolding and aggregation mechanism of α-Syn.
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DOI：
10.1126/science.aat8407
发表时间：
2018-11-02
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
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通讯作者：
Dawson VL
影响因子：
15
作者：
Han W;Schulten K
通讯作者：
Schulten K
DOI：
10.1002/prot.340110305
发表时间：
1991-01-01
期刊：
PROTEINS-STRUCTURE FUNCTION AND GENETICS
影响因子：
--
作者：
ICHIYE, T;KARPLUS, M
通讯作者：
KARPLUS, M
DOI：
10.3233/jpd-179005
发表时间：
2017
期刊：
Journal of Parkinson's disease
影响因子：
--
作者：
Goedert M;Jakes R;Spillantini MG
通讯作者：
Spillantini MG
影响因子：
4.4
作者：
JORGENSEN, WL;CHANDRASEKHAR, J;KLEIN, ML
通讯作者：
KLEIN, ML