Parkin-mediated reduction of nuclear and soluble TDP-43 reverses behavioral decline in symptomatic mice.

Abstract

The transactivation DNA-binding protein (TDP)-43 binds to thousands of mRNAs, but the functional outcomes of this binding remain largely unknown. TDP-43 binds to Park2 mRNA, which expresses the E3 ubiquitin ligase parkin. We previously demonstrated that parkin ubiquitinates TDP-43 and facilitates its translocation from the nucleus to the cytoplasm. Here we used brain penetrant tyrosine kinase inhibitors (TKIs), including nilotinib and bosutinib and showed that they reduce the level of nuclear TDP-43, abrogate its effects on neuronal loss, and reverse cognitive and motor decline. Nilotinib decreased soluble and insoluble TDP-43, while bosutinib did not affect the insoluble level. Parkin knockout mice exhibited high levels of endogenous TDP-43, while nilotinib and bosutinib did not alter TDP-43, underscoring an indispensable role for parkin in TDP-43 sub-cellular localization. These data demonstrate a novel functional relationship between parkin and TDP-43 and provide evidence that TKIs are potential therapeutic candidates for TDP-43 pathologies.