Department of Biology, York Biomedical Research Institute, University of York, Wentworth Way, York YO10 5DD, UK.
Maurice Wohl Clinical Neuroscience Institute, Institute of Psychiatry, Psychology and Neuroscience, King's College London, 125 Coldharbour Lane, Camberwell, London SE5 9NU, UK.
Int J Mol Sci. 2021 Jun 2;22(11):6004. doi: 10.3390/ijms22116004.
TDP-43 is an RNA-binding protein that has been robustly linked to the pathogenesis of a number of neurodegenerative disorders, including amyotrophic lateral sclerosis and frontotemporal dementia. While mutations in the TARDBP gene that codes for the protein have been identified as causing disease in a small subset of patients, TDP-43 proteinopathy is present in the majority of cases regardless of mutation status. This raises key questions regarding the mechanisms by which TDP-43 proteinopathy arises and spreads throughout the central nervous system. Numerous studies have explored the role of a variety of cellular functions on the disease process, and nucleocytoplasmic transport, protein homeostasis, RNA interactions and cellular stress have all risen to the forefront as possible contributors to the initiation of TDP-43 pathogenesis. There is also a small but growing body of evidence suggesting that aggregation-prone TDP-43 can recruit physiological TDP-43, and be transmitted intercellularly, providing a mechanism whereby small-scale proteinopathy spreads from cell to cell, reflecting the spread of clinical symptoms observed in patients. This review will discuss the potential role of the aforementioned cellular functions in TDP-43 pathogenesis, and explore how aberrant pathology may spread, and result in a feed-forward cascade effect, leading to robust TDP-43 proteinopathy and disease.
TDP-43 是一种 RNA 结合蛋白，与多种神经退行性疾病的发病机制密切相关，包括肌萎缩侧索硬化症和额颞叶痴呆。虽然编码该蛋白的 TARDBP 基因突变已被确定为一小部分患者致病的原因，但无论突变状态如何，TDP-43 蛋白病都存在于大多数病例中。这就提出了关于 TDP-43 蛋白病产生和在中枢神经系统中传播的机制的关键问题。许多研究探讨了多种细胞功能在疾病过程中的作用，核质转运、蛋白质稳态、RNA 相互作用和细胞应激都作为 TDP-43 发病机制起始的可能因素而成为研究的前沿。也有少量但不断增加的证据表明，易于聚集的 TDP-43 可以募集生理 TDP-43，并在细胞间传递，提供了一种机制，使小规模的蛋白病从一个细胞传播到另一个细胞，反映了在患者中观察到的临床症状的传播。这篇综述将讨论上述细胞功能在 TDP-43 发病机制中的潜在作用，并探讨异常病理如何传播，并导致强有力的 TDP-43 蛋白病和疾病。
