Laboratory of Molecular and Chemical Biology of Neurodegeneration, Brain Mind Institute, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
ND BioSciences, Epalinges, Switzerland.
Nat Rev Neurosci. 2021 Feb;22(2):111-131. doi: 10.1038/s41583-020-00416-6. Epub 2021 Jan 11.
Lewy bodies (LBs) are α-synuclein (α-syn)-rich intracellular inclusions that are an important pathological hallmark of Parkinson disease and several other neurodegenerative diseases. Increasing evidence suggests that the aggregation of α-syn has a central role in LB formation and is one of the key processes that drive neurodegeneration and pathology progression in Parkinson disease. However, little is known about the mechanisms underlying the formation of LBs, their biochemical composition and ultrastructural properties, how they evolve and spread with disease progression, and their role in neurodegeneration. In this Review, we discuss current knowledge of α-syn pathology, including the biochemical, structural and morphological features of LBs observed in different brain regions. We also review the most used cellular and animal models of α-syn aggregation and pathology spreading in relation to the extent to which they reproduce key features of authentic LBs. Finally, we provide important insights into molecular and cellular determinants of LB formation and spreading, and highlight the critical need for more detailed and systematic characterization of α-syn pathology, at both the biochemical and structural levels. This would advance our understanding of Parkinson disease and other neurodegenerative diseases and allow the development of more-reliable disease models and novel effective therapeutic strategies.
路易体（Lewy bodies，LB）是富含α-突触核蛋白（α-synuclein，α-syn）的细胞内包涵体，是帕金森病和其他几种神经退行性疾病的重要病理学标志。越来越多的证据表明，α-syn 的聚集在 LB 形成中起核心作用，是驱动帕金森病神经退行性变和病理进展的关键过程之一。然而，对于 LB 的形成机制、其生化组成和超微结构特性、在疾病进展过程中如何演变和传播，以及它们在神经退行性变中的作用，人们知之甚少。在这篇综述中，我们讨论了目前对 α-syn 病理学的认识，包括不同脑区观察到的 LB 的生化、结构和形态特征。我们还回顾了最常用于研究 α-syn 聚集和病理传播的细胞和动物模型，以及它们在多大程度上再现了真实 LB 的关键特征。最后，我们深入探讨了 LB 形成和传播的分子和细胞决定因素，并强调了更详细和系统地表征 α-syn 病理学的迫切需要，包括生化和结构水平。这将有助于我们深入了解帕金森病和其他神经退行性疾病，并开发出更可靠的疾病模型和新的有效治疗策略。
