Department of Neurosciences, Leuven Brain Institute (LBI), KU Leuven, Leuven, Belgium.
Laboratory of Neurobiology, VIB-KU Leuven Center for Brain & Disease Research, Leuven, Belgium.
Nat Rev Neurosci. 2021 Apr;22(4):197-208. doi: 10.1038/s41583-021-00431-1. Epub 2021 Mar 2.
Cytoplasmic aggregation of TAR DNA-binding protein 43 (TDP43; also known as TARDBP or TDP-43) is a key pathological feature of several neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). TDP43 typically resides in the nucleus but can shuttle between the nucleus and the cytoplasm to exert its multiple functions, which include regulation of the splicing, trafficking and stabilization of RNA. Cytoplasmic mislocalization and nuclear loss of TDP43 have both been associated with ALS and FTD, suggesting that calibrated levels and correct localization of TDP43 - achieved through an autoregulatory loop and tightly controlled nucleocytoplasmic transport - safeguard its normal function. Furthermore, TDP43 can undergo phase transitions, including its dispersion into liquid droplets and its accumulation into irreversible cytoplasmic aggregates. Thus, autoregulation, nucleocytoplasmic transport and phase transition are all part of an intrinsic control system regulating the physiological levels and localization of TDP43, and together are essential for the cellular homeostasis that is affected in neurodegenerative disease.
细胞质中 TAR DNA 结合蛋白 43（TDP43；也称为 TARDBP 或 TDP-43）的聚集是包括肌萎缩侧索硬化症（ALS）和额颞叶痴呆（FTD）在内的几种神经退行性疾病的关键病理学特征。TDP43 通常位于细胞核内，但可以在核内和细胞质之间穿梭，以发挥其多种功能，包括调节 RNA 的剪接、运输和稳定。TDP43 的细胞质定位错误和核内丢失都与 ALS 和 FTD 有关，这表明 TDP43 的校准水平和正确定位 - 通过自动调节环和严格控制的核质运输来实现 - 可以保护其正常功能。此外，TDP43 可以发生相转变，包括分散成液滴和不可逆的细胞质聚集。因此，自动调节、核质运输和相转变都是调节 TDP43 生理水平和定位的内在控制系统的一部分，共同为受神经退行性疾病影响的细胞内稳态所必需。
