Key Laboratory of RNA Innovation, Science and Engineering, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai 200031, China.
University of Chinese Academy of Sciences, Beijing 100049, China.
Int J Mol Sci. 2024 Nov 18;25(22):12380. doi: 10.3390/ijms252212380.
Pathological aggregation of a specific protein into insoluble aggregates is a common hallmark of various neurodegenerative diseases (NDDs). In the earlier literature, each NDD is characterized by the aggregation of one or two pathogenic proteins, which can serve as disease-specific biomarkers. The aggregation of these specific proteins is thought to be a major cause of or deleterious result in most NDDs. However, accumulating evidence shows that a pathogenic protein can interact and co-aggregate with other pathogenic proteins in different NDDs, thereby contributing to disease onset and progression synergistically. During the past years, more than one type of NDD has been found to co-exist in some individuals, which may increase the complexity and pathogenicity of these diseases. This article reviews and discusses the biochemical characteristics and molecular mechanisms underlying the co-aggregation and co-pathologies associated with TDP-43 pathology. The TDP-43 aggregates, as a hallmark of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD), can often be detected in other NDDs, such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD) and spinocerebellar ataxia type 2 (SCA2). In many cases, TDP-43 is shown to interact and co-aggregate with multiple pathogenic proteins in vitro and in vivo. Furthermore, the co-occurrence and co-aggregation of TDP-43 with other pathogenic proteins have important consequences that may aggravate the diseases. Thus, the current viewpoint that the co-aggregation of TDP-43 with other pathogenic proteins in NDDs and their relevance to disease progression may gain insights into the patho-mechanisms and therapeutic potential of various NDDs.
特定蛋白质的病理性聚集形成不溶性聚集体是各种神经退行性疾病（NDDs）的共同特征。在早期文献中，每种 NDD 的特征是一种或两种致病性蛋白质的聚集，这些蛋白质可以作为疾病特异性生物标志物。这些特定蛋白质的聚集被认为是大多数 NDD 的主要原因或有害结果。然而，越来越多的证据表明，一种致病性蛋白质可以与不同 NDD 中的其他致病性蛋白质相互作用并共同聚集，从而协同促进疾病的发生和进展。在过去的几年中，已经发现一种以上类型的 NDD 存在于某些个体中，这可能会增加这些疾病的复杂性和致病性。本文综述和讨论了 TDP-43 病理学相关的共聚集和共病理学的生化特征和分子机制。TDP-43 聚集体作为肌萎缩侧索硬化症（ALS）和额颞叶变性（FTLD）的标志，通常可以在其他 NDD 中检测到，如阿尔茨海默病（AD）、帕金森病（PD）、亨廷顿病（HD）和脊髓小脑性共济失调 2 型（SCA2）。在许多情况下，TDP-43 在体外和体内被证明与多种致病性蛋白质相互作用和共同聚集。此外，TDP-43 与其他致病性蛋白质的共同发生和聚集具有重要后果，可能会加重疾病。因此，目前认为 TDP-43 与 NDD 中的其他致病性蛋白质的共聚集及其与疾病进展的相关性可能深入了解各种 NDD 的病理机制和治疗潜力。
