Department of Cell and Molecular Biology, St Jude Children's Research Hospital, Memphis, TN, USA.
Howard Hughes Medical Institute, Chevy Chase, MD, USA.
Nat Rev Neurol. 2019 May;15(5):272-286. doi: 10.1038/s41582-019-0157-5.
Biomolecular condensation arising through phase transitions has emerged as an essential organizational strategy that governs many aspects of cell biology. In particular, the role of phase transitions in the assembly of large, complex ribonucleoprotein (RNP) granules has become appreciated as an important regulator of RNA metabolism. In parallel, genetic, histopathological and cell and molecular studies have provided evidence that disturbance of phase transitions is an important driver of neurological diseases, notably amyotrophic lateral sclerosis (ALS), but most likely also other diseases. Indeed, our growing knowledge of the biophysics underlying biological phase transitions suggests that this process offers a unifying mechanism to explain the numerous and diverse disturbances in RNA metabolism that have been observed in ALS and some related diseases - specifically, that these diseases are driven by disturbances in the material properties of RNP granules. Here, we review the evidence for this hypothesis, emphasizing the reciprocal roles in which disease-related protein and disease-related RNA can lead to disturbances in the material properties of RNP granules and consequent pathogenesis. Additionally, we review evidence that implicates aberrant phase transitions as a contributing factor to a larger set of neurodegenerative diseases, including frontotemporal dementia, certain repeat expansion diseases and Alzheimer disease.
生物分子凝聚通过相变出现已经成为一种基本的组织策略，控制着细胞生物学的许多方面。特别是，相变在大型复杂核糖核蛋白（RNP）颗粒组装中的作用已经被认为是 RNA 代谢的重要调节剂。与此同时，遗传、组织病理学以及细胞和分子研究提供了证据表明，相变的干扰是神经疾病的一个重要驱动因素，特别是肌萎缩侧索硬化症（ALS），但很可能也是其他疾病。事实上，我们对生物相变背后的生物物理知识的不断增长表明，这一过程提供了一个统一的机制来解释在 ALS 和一些相关疾病中观察到的大量和多样化的 RNA 代谢紊乱——具体而言，这些疾病是由 RNP 颗粒的物质性质紊乱驱动的。在这里，我们回顾了这一假说的证据，强调了疾病相关蛋白和疾病相关 RNA 可以在其中发挥相互作用的角色，导致 RNP 颗粒物质性质的紊乱，并由此导致发病机制。此外，我们还回顾了证据表明，异常相变是更大一组神经退行性疾病的一个促成因素，包括额颞叶痴呆、某些重复扩展疾病和阿尔茨海默病。
