Department of Pharmacology and Chemical Biology, Baylor College of Medicine, Houston, TX 77030, USA.
Int J Mol Sci. 2023 Feb 8;24(4):3380. doi: 10.3390/ijms24043380.
Cellular deposition of protein aggregates, one of the hallmarks of neurodegeneration, disrupts cellular functions and leads to neuronal death. Mutations, posttranslational modifications, and truncations are common molecular underpinnings in the formation of aberrant protein conformations that seed aggregation. The major proteins involved in neurodegeneration include amyloid beta (Aβ) and tau in Alzheimer's disease, α-synuclein in Parkinson's disease, and TAR DNA-binding protein (TDP-43) in amyotrophic lateral sclerosis (ALS). These proteins are described as intrinsically disordered and possess enhanced ability to partition into biomolecular condensates. In this review, we discuss the role of protein misfolding and aggregation in neurodegenerative diseases, specifically highlighting implications of changes to the primary/secondary (mutations, posttranslational modifications, and truncations) and the quaternary/supramolecular (oligomerization and condensation) structural landscapes for the four aforementioned proteins. Understanding these aggregation mechanisms provides insights into neurodegenerative diseases and their common underlying molecular pathology.
蛋白质聚集体在神经退行性变中的沉积是其特征之一，它会破坏细胞功能并导致神经元死亡。在形成异常蛋白质构象从而引发聚集的过程中，突变、翻译后修饰和截断是常见的分子基础。涉及神经退行性变的主要蛋白质包括阿尔茨海默病中的淀粉样β（Aβ）和tau、帕金森病中的α-突触核蛋白以及肌萎缩侧索硬化症（ALS）中的 TAR DNA 结合蛋白（TDP-43）。这些蛋白质被描述为固有无序，并且具有增强的能力将其分配到生物分子凝聚物中。在这篇综述中，我们讨论了蛋白质错误折叠和聚集在神经退行性疾病中的作用，特别强调了对一级/二级结构（突变、翻译后修饰和截断）和四级/超分子结构（寡聚化和凝聚）的改变对上述四种蛋白质的影响。了解这些聚集机制为神经退行性疾病及其常见的潜在分子病理学提供了深入的认识。
