Nuclear TDP-43 causes neuronal toxicity by escaping from the inhibitory regulation by hnRNPs.

Dysregulation of transactive response DNA-binding protein-43 (TDP-43) is thought to be linked to the pathogenesis of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). TDP-43 normally localizes in the nucleus but its main localization shifts to the cytoplasm in most affected cells of ALS and FTLD patients. It is not yet known whether nuclear or cytoplasmic TDP-43 is responsible for TDP-43-induced neurotoxicity. In this study, we show that nuclear TDP-43 causes TDP-43 neurotoxicity. DNA/RNA-binding and dimerization of TDP-43 are both essential for TDP-43-induced cell death. Moreover, endogenous heterogeneous nuclear ribonucleoprotein-U (hnRNP-U) binds to TDP-43 and knocking-down of hnRNP-U induces neurotoxicity, whereas overexpression of hnRNP-U or hnRNP-A2 inhibits TDP-43-induced neurotoxicity. In addition, hnRNP-U inhibits TDP-43-mediated alterations in splicing of POLDIP3 mRNA. Altogether, these results suggest that nuclear TDP-43 becomes neurotoxic by escaping from the inhibitory regulation by hnRNPs.

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