Department of Neurology of the Second Affiliated Hospital and Department of Human Anatomy, Histology and Embryology, Zhejiang University School of Medicine, Hangzhou, 310058, China.
Department of Physiology and Department of Cardiology of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310058, China.
Neurosci Bull. 2024 Feb;40(2):241-254. doi: 10.1007/s12264-023-01115-9. Epub 2023 Sep 27.
The accumulation and spread of prion-like proteins is a key feature of neurodegenerative diseases (NDs) such as Alzheimer's disease, Parkinson's disease, or Amyotrophic Lateral Sclerosis. In a process known as 'seeding', prion-like proteins such as amyloid beta, microtubule-associated protein tau, α-synuclein, silence superoxide dismutase 1, or transactive response DNA-binding protein 43 kDa, propagate their misfolded conformations by transforming their respective soluble monomers into fibrils. Cellular and molecular evidence of prion-like propagation in NDs, the clinical relevance of their 'seeding' capacities, and their levels of contribution towards disease progression have been intensively studied over recent years. This review unpacks the cyclic prion-like propagation in cells including factors of aggregate internalization, endo-lysosomal leaking, aggregate degradation, and secretion. Debates on the importance of the role of prion-like protein aggregates in NDs, whether causal or consequent, are also discussed. Applications lead to a greater understanding of ND pathogenesis and increased potential for therapeutic strategies.
朊病毒样蛋白的积累和扩散是阿尔茨海默病、帕金森病或肌萎缩性侧索硬化症等神经退行性疾病（NDs）的一个关键特征。在一个被称为“播种”的过程中，朊病毒样蛋白，如淀粉样β、微管相关蛋白 tau、α-突触核蛋白、沉默超氧化物歧化酶 1 或反式激活反应 DNA 结合蛋白 43 kDa，通过将其各自的可溶性单体转化为纤维来传播其错误折叠的构象。近年来，人们对 NDs 中朊病毒样传播的细胞和分子证据、其“播种”能力的临床相关性以及它们对疾病进展的贡献程度进行了深入研究。这篇综述阐述了细胞内的循环朊病毒样传播，包括聚集体内化、内溶酶体渗漏、聚集体降解和分泌的因素。还讨论了朊病毒样蛋白聚集体在 NDs 中是否具有因果关系的重要性的争议。应用将有助于更好地理解 ND 的发病机制，并增加治疗策略的潜力。
