Department of Biotechnology, National Institute of Pharmaceutical Education and Research, Raebareli (NIPER-R), Lucknow-226002, Uttar Pradesh, India.
ACS Chem Biol. 2024 Oct 18;19(10):2118-2130. doi: 10.1021/acschembio.4c00365. Epub 2024 Oct 7.
Protein misfolding and aggregation are the hallmarks of neurodegenerative diseases including Huntington's disease, Parkinson's disease, Alzheimer's disease, and prion diseases. A crowded cellular environment plays a crucial role in modulating protein aggregation processes and the pathological aggregation of proteins linked to different neurodegenerative disorders. Here, we review recent studies examining the effects of various crowding agents, such as polysaccharides, polyethylene glycol, and proteins like BSA and lysozyme on the behaviors of aggregation of several amyloidogenic peptides and proteins, including amylin, huntingtin, tau, α-synuclein, prion, and amyloid-β. We also summarize how the aggregation kinetics, thermodynamic stability, and morphology of amyloid fibrils are altered significantly in the presence of crowding agents. In addition, we also discuss the molecular basis underlying the modulation of amyloidogenic aggregation, focusing on changes in the protein conformation, and the nucleation mechanism. The molecular understanding of the effects of macromolecular crowding on amyloid aggregation is essential for revealing disease pathologies and identifying possible therapeutic targets. Thus, this review offers a perspective on the complex interplay between protein aggregation and the crowded cellular environment and explains the relevance of crowding in the context of neurodegenerative disorders.
蛋白质错误折叠和聚集是包括亨廷顿病、帕金森病、阿尔茨海默病和朊病毒病在内的神经退行性疾病的标志。拥挤的细胞环境在调节蛋白质聚集过程中起着至关重要的作用，并且与不同神经退行性疾病相关的蛋白质病理性聚集有关。在这里，我们回顾了最近的研究，这些研究检查了各种拥挤剂（如多糖、聚乙二醇以及像 BSA 和溶菌酶这样的蛋白质）对几种淀粉样肽和蛋白质（包括胰岛淀粉样多肽、亨廷顿蛋白、tau 蛋白、α-突触核蛋白、朊病毒和淀粉样-β）聚集行为的影响。我们还总结了拥挤剂如何显著改变淀粉样纤维的聚集动力学、热力学稳定性和形态。此外，我们还讨论了淀粉样蛋白聚集的调节的分子基础，重点是蛋白质构象的变化和成核机制。对大分子拥挤对淀粉样蛋白聚集影响的分子理解对于揭示疾病病理学和确定可能的治疗靶点至关重要。因此，本综述提供了一个关于蛋白质聚集和拥挤细胞环境之间复杂相互作用的视角，并解释了拥挤在神经退行性疾病中的相关性。
