PTK2 regulates the UPS impairment via p62 phosphorylation in TDP-43 proteinopathy

摘要: TDP-43 proteinopathy is a common feature in variety of neurodegenerative disorders including ALS, FTLD, and AD. However, the molecular mechanisms underlying TDP-43-induced neurotoxicity are largely unknown. In this study, we demonstrated that induces impairment UPS evidenced by an accumulation ubiquitinated proteins reduction proteasome activity neuronal cells. Through kinase inhibitor screening, identified PTK2 as suppressor induced impairment. Importantly, inhibition significantly reduces ubiquitin aggregates attenuated cytotoxicity Drosophila model proteinopathy. We further phosphorylation p62 at serine 403 increased upon overexpression dependent on activation Moreover, expressing non-phosphorylated form represses poly-ubiquitinated addition, TBK1, which phosphorylates S403 p62, ameliorates Taken together, targeting PTK2-TBK1-p62 axis may represent novel therapeutic intervention for diseases with