Mechanisms of TDP-43 Proteinopathy Onset and Propagation

International Journal of Molecular Sciences

Han-Jou Chen¹  Jacqueline C. Mitchell² 

[1] 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;

关键词: TDP-43;    neurodegeneration;    ALS;    frontotemporal dementia;    proteinopathy;   

DOI  :  10.3390/ijms22116004

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown