Department of Neuroscience, Weinberg ALS Center, Vickie and Jack Farber Institute for Neuroscience, Thomas Jefferson University, Philadelphia, PA, USA.
Department of Neuroscience, Sheffield Institute for Translational Neuroscience (SITraN), University of Sheffield, Sheffield, UK.
EMBO J. 2021 May 17;40(10):e106389. doi: 10.15252/embj.2020106389. Epub 2021 Mar 31.
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder whose exact causative mechanisms are still under intense investigation. Several lines of evidence suggest that the anatomical and temporal propagation of pathological protein species along the neural axis could be among the main driving mechanisms for the fast and irreversible progression of ALS pathology. Many ALS-associated proteins form intracellular aggregates as a result of their intrinsic prion-like properties and/or following impairment of the protein quality control systems. During the disease course, these mutated proteins and aberrant peptides are released in the extracellular milieu as soluble or aggregated forms through a variety of mechanisms. Internalization by recipient cells may seed further aggregation and amplify existing proteostatic imbalances, thus triggering a vicious cycle that propagates pathology in vulnerable cells, such as motor neurons and other susceptible neuronal subtypes. Here, we provide an in-depth review of ALS pathology with a particular focus on the disease mechanisms of seeding and transmission of the most common ALS-associated proteins, including SOD1, FUS, TDP-43, and C9orf72-linked dipeptide repeats. For each of these proteins, we report historical, biochemical, and pathological evidence of their behaviors in ALS. We further discuss the possibility to harness pathological proteins as biomarkers and reflect on the implications of these findings for future research.
肌萎缩侧索硬化症（ALS）是一种致命的神经退行性疾病，其确切的致病机制仍在深入研究中。有几方面的证据表明，沿着神经轴的病理性蛋白种的解剖和时间传播可能是 ALS 病理快速和不可逆转进展的主要驱动机制之一。许多与 ALS 相关的蛋白质由于其内在的类朊病毒特性和/或蛋白质量控制系统受损，会形成细胞内聚集体。在疾病过程中，这些突变蛋白和异常肽通过多种机制以可溶性或聚集形式释放到细胞外环境中。通过受体细胞内化可能会引发进一步的聚集，并放大现有的蛋白质平衡失调，从而触发一个恶性循环，在易受影响的细胞（如运动神经元和其他易感神经元亚型）中传播病理学。在这里，我们深入综述了 ALS 病理学，特别关注最常见的 ALS 相关蛋白（包括 SOD1、FUS、TDP-43 和 C9orf72 相关二肽重复）的播种和传播的疾病机制。对于这些蛋白质中的每一种，我们报告了它们在 ALS 中的历史、生化和病理学证据。我们进一步讨论了将病理性蛋白作为生物标志物的可能性，并反思了这些发现对未来研究的意义。
