ABSTRACT

Ribonucleoprotein (RNP) assemblies are ubiquitous in eukaryotic cells and have functions throughout RNA transcription, splicing, and stability. Of the RNA-binding proteins that form RNPs, TAR DNA-binding protein of 43 kD (TDP43) is of particular interest due to its essential nature and its association with disease. TDP43 plays critical roles in RNA metabolism, many of which require its recruitment to RNP granules such as stress granules, myo-granules, and neuronal transport granules. Moreover, the presence of cytoplasmic TDP43-positive inclusions is a pathological hallmark of several neurodegenerative diseases. Despite the pervasiveness of TDP43 aggregates, TDP43 mutations are exceedingly rare, suggesting that aggregation may be linked to dysregulation of TDP43 function. Oligomerization is a part of normal TDP43 function; thus, it is of interest to understand what triggers the irreversible aggregation that is seen in disease. Herein, we examine TDP43 functions, particularly in RNP granules, and the mechanisms which may explain pathological TDP43 aggregation.

摘要

核糖核蛋白 (RNP) 组装体在真核细胞中普遍存在，并在 RNA 转录、剪接和稳定性方面发挥着重要作用。在形成 RNP 的 RNA 结合蛋白中，43 kD 的 TAR DNA 结合蛋白 (TDP43) 由于其基本性质及其与疾病的相关性而受到特别关注。TDP43 在 RNA 代谢中发挥着关键作用，其中许多需要将其招募到 RNP 颗粒，例如应激颗粒、肌颗粒和神经元运输颗粒。此外，细胞质 TDP43 阳性包涵体的存在是几种神经退行性疾病的病理标志。尽管 TDP43 聚集体普遍存在，但 TDP43 突变极为罕见，这表明聚集可能与 TDP43 功能失调有关。寡聚化是 TDP43 正常功能的一部分；因此，了解是什么触发了疾病中所见的不可逆聚集是很有意义的。在此，我们检查了 TDP43 的功能，特别是在 RNP 颗粒中，以及可能解释病理性 TDP43 聚集的机制。