摘 要
神经退行性疾病是一类以蛋白质异常聚集为特征的复杂疾病，其发病机制尚未完全阐明。本研究旨在系统探讨神经退行性疾病中蛋白质聚集的分子机制及其调控网络。通过整合生物信息学分析、分子动力学模拟和实验验证等多学科方法，重点研究了α-突触核蛋白、tau蛋白和TDP-43等关键致病蛋白的构象转变过程及其与细胞微环境的相互作用。研究发现，蛋白质错误折叠不仅受内在序列特征的影响，还与氧化应激、金属离子浓度等外部因素密切相关。通过构建多尺度计算模型，揭示了蛋白质聚集过程中的关键中间态及其能量景观特征。实验结果表明，特定分子伴侣和小分子抑制剂可有效调控蛋白质聚集路径，为疾病干预提供了新的靶点。本研究的创新之处在于建立了蛋白质聚集的多层次研究框架，阐明了环境因素在蛋白质构象转变中的调控作用，并筛选出具有潜在治疗价值的化合物。
关键词：神经退行性疾病 蛋白质聚集 分子机制
Abstract
Neurodegenerative diseases are a class of complex diseases characterized by abnormal aggregation of proteins, whose pathogenesis has not been fully elucidated. This study aimed to systematically explore the molecular mechanisms of protein aggregation and their regulatory networks in neurodegenerative diseases. By integrating multidisciplinary approaches including bioinformational analysis, molecular dynamics simulation, and experimental validation, we focused on conformational transition processes and their interactions with the cellular microenvironment of key pathogenic proteins like α -synuclein, tau, and TDP-43. It is found that protein misfolding is not only affected by intrinsic sequence features, but also closely related to external factors such as oxidative stress and me tal ion concentration. The key intermediate states during protein aggregation and their energy landscape features. The experimental results show that specific molecular chaperones and small molecule inhibitors can effectively regulate protein aggregation paths, providing new targets for disease intervention. The innovation of this study is the establishment of a multi-level research fr amework for protein aggregation, elucidating the regulatory role of environmental factors in protein conformational transition, and the screening of compounds with potential therapeutic value.
Keyword: Neurodegenerative diseases Protein aggregation molecular mechanism
目 录
1绪论 1
1.1研究背景 1
1.2研究现状 1
1.3研究方法与技术路线 2
2神经退行性疾病相关蛋白的病理特征 2
2.1α-突触核蛋白在帕金森病中的聚集机制 2
2.2Tau蛋白在阿尔茨海默病中的异常折叠 3
2.3TDP-43在肌萎缩侧索硬化症中的病理表现 3
3蛋白质聚集的分子机制研究 4
3.1蛋白质错误折叠的分子基础 4
3.2淀粉样纤维形成的动力学过程 5
3.3蛋白质聚集体的细胞毒性机制 5
4蛋白质聚集的调控与干预策略 6
4.1分子伴侣系统对蛋白质折叠的调控作用 6
4.2自噬系统在清除异常蛋白中的作用 6
4.3靶向蛋白质聚集的治疗策略探索 7
5结论 8
参考文献 9
致谢 10
神经退行性疾病是一类以蛋白质异常聚集为特征的复杂疾病，其发病机制尚未完全阐明。本研究旨在系统探讨神经退行性疾病中蛋白质聚集的分子机制及其调控网络。通过整合生物信息学分析、分子动力学模拟和实验验证等多学科方法，重点研究了α-突触核蛋白、tau蛋白和TDP-43等关键致病蛋白的构象转变过程及其与细胞微环境的相互作用。研究发现，蛋白质错误折叠不仅受内在序列特征的影响，还与氧化应激、金属离子浓度等外部因素密切相关。通过构建多尺度计算模型，揭示了蛋白质聚集过程中的关键中间态及其能量景观特征。实验结果表明，特定分子伴侣和小分子抑制剂可有效调控蛋白质聚集路径，为疾病干预提供了新的靶点。本研究的创新之处在于建立了蛋白质聚集的多层次研究框架，阐明了环境因素在蛋白质构象转变中的调控作用，并筛选出具有潜在治疗价值的化合物。
关键词：神经退行性疾病 蛋白质聚集 分子机制
Abstract
Neurodegenerative diseases are a class of complex diseases characterized by abnormal aggregation of proteins, whose pathogenesis has not been fully elucidated. This study aimed to systematically explore the molecular mechanisms of protein aggregation and their regulatory networks in neurodegenerative diseases. By integrating multidisciplinary approaches including bioinformational analysis, molecular dynamics simulation, and experimental validation, we focused on conformational transition processes and their interactions with the cellular microenvironment of key pathogenic proteins like α -synuclein, tau, and TDP-43. It is found that protein misfolding is not only affected by intrinsic sequence features, but also closely related to external factors such as oxidative stress and me tal ion concentration. The key intermediate states during protein aggregation and their energy landscape features. The experimental results show that specific molecular chaperones and small molecule inhibitors can effectively regulate protein aggregation paths, providing new targets for disease intervention. The innovation of this study is the establishment of a multi-level research fr amework for protein aggregation, elucidating the regulatory role of environmental factors in protein conformational transition, and the screening of compounds with potential therapeutic value.
Keyword: Neurodegenerative diseases Protein aggregation molecular mechanism
目 录
1绪论 1
1.1研究背景 1
1.2研究现状 1
1.3研究方法与技术路线 2
2神经退行性疾病相关蛋白的病理特征 2
2.1α-突触核蛋白在帕金森病中的聚集机制 2
2.2Tau蛋白在阿尔茨海默病中的异常折叠 3
2.3TDP-43在肌萎缩侧索硬化症中的病理表现 3
3蛋白质聚集的分子机制研究 4
3.1蛋白质错误折叠的分子基础 4
3.2淀粉样纤维形成的动力学过程 5
3.3蛋白质聚集体的细胞毒性机制 5
4蛋白质聚集的调控与干预策略 6
4.1分子伴侣系统对蛋白质折叠的调控作用 6
4.2自噬系统在清除异常蛋白中的作用 6
4.3靶向蛋白质聚集的治疗策略探索 7
5结论 8
参考文献 9
致谢 10
