The role of X phosphatase in ALS/FTD

초록

Abnormal cytoplasmic accumulation of TAR DNA-binding protein 43 (TDP-43) is a common feature in neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), whereas the molecular mechanisms underlying TDP-43– induced neurotoxicity remain unclear. Here, we show that TDP-43–induced neurotoxicity, both in vitro and in vivo, is alleviated by inhibition of X phosphatase. Overexpression of TDP-43 in neuronal cells impaired the ubiquitin-proteasome system (UPS), leading to cytoplasmic aggregation and accumulation of ubiquitinated proteins, whereas inhibition of X phosphatase restored UPS by activating the autophagy-lysosomal pathway (ALP). X phosphatase inhibition also reduced mitochondrial dysfunction and neuronal toxicity. In Drosophila models, reduced lifespan and locomotor deficits caused by TDP-43 were rescued by X phosphatase inhibition. Furthermore, siRNA screening identified a novel target interacting with X phosphatase, suggesting an additional regulatory mechanism in TDP-43 pathology. Taken together, these findings suggest that the expression of X phosphatase plays a crucial role in modulating TDP-43-induced pathological features in ALS/FTD.