Identification of Thioredoxin 1 as a therapeutic target for TDP-43 proteopathy

초록

Transactive response (TAR) DNA-binding protein 43 (TDP-43) is widely expressed nuclear protein which regulates the expression of a variety of genes via regulating RNA splicing, trafficking, and/or stabilization. Under pathological context, TDP-43 is mislocalized to cytoplasm, and aggregated into insoluble inclusions. The aggregation of TDP-43 induces oxidative stress that leads to neurodegeneration in various neurodegenerative diseases, such as Amyotrophic lateral sclerosis (ALS), Frontotemporal dementia (FTD), and Alzheimer's disease (AD). However, our understanding of the pathological mechanisms of TDP-43 proteinopathies remains elusive. Therefore, it is critical to identify the molecular mechanisms of TDP-43 pathology to develop novel therapeutic interventions. We developed a cellular model of TDP-43 proteinopathies using mouse neuronal Neuro 2a cells. Using this cellular model, we identified overexpression of Thiredoxin 1 (TRX1) decreased TDP-43 protein expression level and cytosolic TDP-43 mislocation. Furthermore, we validate that Trx1 reduces reactive oxygen species level mitigated with TDP-43 overexpression. Taken together, Our data suggest that TRX1 is a therapeutic target of TDP-43 pathology and may represent a novel therapeutic target for TDP-43 proteinopathies.