Li Dan, Liu Cong
Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Ministry of Education, Shanghai Jiao Tong University, Shanghai, China.
Zhangjiang Institute for Advanced Study, Shanghai Jiao Tong University, Shanghai, China.
Nat Rev Neurosci. 2022 Sep;23(9):523-534. doi: 10.1038/s41583-022-00603-7. Epub 2022 May 30.
Amyloid proteins, which are considered 'villains' in many neurodegenerative diseases, form enigmatic pathological strains that underlie disease pathogenesis and progression. Recent technical advances in cryogenic electron microscopy and solid-state NMR spectroscopy have enabled the high-resolution structures of full-length amyloid fibrils to be determined, initiating an era in which we have the opportunity to gain atomic-level structural understanding of pathogenic protein aggregation in neurodegenerative diseases. In this Review, we aim to explain the clinicopathological heterogeneity of neurodegenerative diseases by considering the polymorphic structures of amyloid fibrils. We decipher the structural basis for the generation of fibril polymorphs, how the fibril polymorphs differ in different disease contexts and how conformational changes alter the pathology caused by amyloid proteins during disease progression. Finally, we evaluate how this knowledge might aid clinical diagnostic and therapeutic strategies to treat neurodegenerative diseases.
淀粉样蛋白在许多神经退行性疾病中被视为“罪魁祸首”，它们形成神秘的病理菌株，是疾病发病机制和进展的基础。低温电子显微镜和固态核磁共振光谱技术的最新进展使得全长淀粉样纤维的高分辨率结构得以确定，开启了一个我们有机会在原子水平上了解神经退行性疾病中致病蛋白聚集结构的时代。在这篇综述中，我们旨在通过考虑淀粉样纤维的多态结构来解释神经退行性疾病的临床病理异质性。我们解读了纤维多态性产生的结构基础、不同疾病背景下纤维多态性的差异，以及构象变化如何在疾病进展过程中改变淀粉样蛋白引起的病理学。最后，我们评估这些知识如何有助于治疗神经退行性疾病的临床诊断和治疗策略。
