The Role Of X Phosphatase In ALS/FTD

초록

Background TAR DNA-binding protein 43 (TDP-43) is a protein associated with neurodegenerative disease such as ALS. TDP-43 is involved in multiple normal biological function including RNA processing and transcriptional regulation, while the cytoplasmic aggregation of TDP-43 in neuron is known as hallmark of ALS. Although TDP-43 pathological has been shown to contribute to the degeneration of in neurodegenerative diseases, the mechanism mediating the TDP-43 induced neurotoxicity remains unknown. A previous study reported that the X phosphatase inhibition in neurodegenerative diseases prevented multiple mechanisms such as ER-stress and neuroinflammation. Method In this study, we evaluated the effect of X phosphatase inhibition on TDP-43-induced neuronal cell death both in vitro and in vivo. Neuro-2a cell were transfected with TDP-43 and then treated with X phosphatase inhibitor. Flow cytometry, TMRE staining, and mitochondrial dysfunction analysis (Seahorse XF analyzer) were analyzed to measure the effect of the inhibitors. We also measured survival and climbing ability in Drosophila model in which TDP-43 was expressed in adult neurons. Results The overexpression of TDP-43 in neuronal cells leads to UPS impairment, as evidenced by an increase in cytoplasmic TDP-43 aggregation and the accumulation of ubiquitinated proteins. However, we investigated that inhibition of X phosphatase in neuronal cell restores TDP-43 impairment though activation of the autophagy-lysosomal pathway activation. We also showed that X phosphatase inhibition attenuated TDP-43-induced neuronal toxicity and mitochondria dysfunction. Moreover, in TDP-43-expressing drosophila models, reduced the lifespan and locomotion were mitigated in the presence of X phosphatase inhibition models. Consistent with this result, the use of X phosphatase-expressing N2a stable cells transfected with TDP-43 affects neurotoxicity and UPS impairment. In addition, we identified a novel target that interacts with X phosphatase using siRNA screening. Conclusions Taken together, these finding suggest that the expression of X phosphatase plays a crucial role in modulating TDP-43 induced pathological features in ALS. This indicates that targeting X phosphatase could be a promising therapeutic approach in mitigating TDP-43-associated neurotoxicity.