Alzheimer's Research UK UCL Drug Discovery Institute and Department of Neuromuscular Diseases, University College London, The Cruciform Building, Gower Street, London, WC1E 6BT, UK.
Reta Lila Weston Institute of Neurological Studies and Department of Clinical and Movement Neuroscience, University College London, Queen Square Institute of Neurology, 1 Wakefield Street, London, WC1N 1PJ, UK.
Neurochem Int. 2020 Nov;140:104819. doi: 10.1016/j.neuint.2020.104819. Epub 2020 Aug 5.
Neurodegenerative diseases are a group of chronic, progressive, age-related disorders that are becoming increasingly prevalent in the ageing population. Despite the variety of clinical features observed, neurodegenerative diseases are characterised by protein aggregation and deposition at the molecular level. The nature of such intracellular protein aggregates is dependent on disease type and specific to disease subtype. Frontotemporal dementia and amyotrophic lateral sclerosis (ALS) are two overlapping neurodegenerative diseases, exhibiting pathological aggregates commonly composed of the proteins: Fused in Sarcoma (FUS) or Transactive Response DNA Binding Protein of 43 KDa (TDP-43). The presence of these protein aggregates in late disease stages is suggestive of a converging underlying mechanism of pathology across diseases involving disrupted proteostasis. Despite this, at present there are no effective therapeutics for the diseases, with current treatment strategies generally tending to be only for symptom management. An area of research that has gained increased interest in recent years is the formation and maintenance of ribonucleoprotein (RNP) granules. These are membraneless organelles that consist of RNA and protein elements, which can be either constitutively expressed (such as nuclear paraspeckles) or upregulated under conditions of cellular stress as an adaptive response (such as cytoplasmic stress granules). RNA-binding proteins are a key component of RNP granules, and crucially some of which, for example FUS and TDP-43, are also neurodegenerative disease-associated proteins. Therefore, a better understanding of RNA-binding proteins in RNP granule formation and the regulation and maintenance of RNP granule biophysical properties and dynamics may provide insights into mechanisms contributing to disrupted proteostasis in neurodegenerative pathology; and thus open up new avenues for therapeutic discovery and development. This review will focus on stress granule and paraspeckle RNP granules, and discuss their possible contribution to pathology in cases of frontotemporal dementia and ALS.
神经退行性疾病是一组慢性、进行性、与年龄相关的疾病，在老年人群中越来越普遍。尽管观察到的临床特征多种多样，但神经退行性疾病的特征是在分子水平上蛋白质聚集和沉积。这种细胞内蛋白质聚集体的性质取决于疾病类型，并且特定于疾病亚型。额颞叶痴呆和肌萎缩侧索硬化症（ALS）是两种重叠的神经退行性疾病，表现出常见的病理聚集物，通常由融合肉瘤（FUS）或 43 kDa 转录激活反应 DNA 结合蛋白（TDP-43）组成。在疾病晚期出现这些蛋白质聚集体表明，涉及蛋白质稳态破坏的疾病具有潜在的趋同病理机制。尽管如此，目前这些疾病没有有效的治疗方法，目前的治疗策略通常仅用于症状管理。近年来，一个越来越受到关注的研究领域是核糖核蛋白（RNP）颗粒的形成和维持。这些是无膜细胞器，由 RNA 和蛋白质元素组成，可以是组成型表达的（如核核斑），也可以在细胞应激条件下上调作为适应性反应（如细胞质应激颗粒）。RNA 结合蛋白是 RNP 颗粒的关键组成部分，至关重要的是，其中一些，例如 FUS 和 TDP-43，也是神经退行性疾病相关蛋白。因此，更好地了解 RNP 颗粒形成中的 RNA 结合蛋白以及 RNP 颗粒生物物理特性和动力学的调节和维持，可能有助于深入了解导致神经退行性病理中蛋白质稳态破坏的机制；并为治疗发现和开发开辟新途径。本综述将重点讨论应激颗粒和核斑 RNP 颗粒，并讨论它们在额颞叶痴呆和 ALS 病例中的病理可能的贡献。
