Endogenous TDP-43 localized to stress granules can subsequently form protein aggregates

摘要: Abstract TDP-43 proteinopathies are characterized by loss of nuclear and accumulation the protein in cytosol as ubiquitinated aggregates. These aggregates may have an important role subsequent neuronal degeneration motor neuron disease, frontotemporal dementia potentially other neurodegenerative diseases. Although cellular mechanisms driving abnormal not understood, recent studies shown that early change to metabolism disease be cytosolic RNA stress granules (SGs). However, it is unclear whether these SGs progresses become irreversible observed patients. We recently paraquat-treated cells a useful model for examining SG localization. In this study, we used paraquat examine if endogenous can progress more stable found after treatment HeLa overnight with paraquat, co-localized together ubiquitous marker, human antigen R (HuR). further incubation paraquat-free, conditioned medium 6 h, HuR-positive were rarely detected yet positive remained present. The majority ubiquitin. Further evidence persistence was obtained treating cultures cycloheximide treatment. Cycloheximide abolished nearly all HuR aggregation (SGs) but large TDP-43-positive remained. Finally, showed addition ERK JNK inhibitors blocked formation, while 24 h exposure failed reverse accumulation. This failure most likely due maximal activation kinases at 4 h post-paraquat findings provide strong once accumulates SGs, has potential neurons proteinopathies. therapeutic opportunity inhibit transition from aggregate.