HIPK2 loss promotes TDP-43 cytoplasmic mis-localization through MAPK-pathway and is associated with TDP-43 proteinopathy in vivo

Homeodomain Interacting Protein Kinase 2 (HIPK2) is a stress sensor kinase that has emerged as a key regulator of neuronal homeostasis and survival. In this study, we investigated the role of HIPK2 in neurodegeneration using both in vivo and in vitro models. We show that Hipk2 knockout mice exhibit motor and cognitive deficits reminiscent of those observed in Amyotrophic Lateral Sclerosis (ALS), which are accompanied by cytoplasmic mis-localization of TDP-43, a hallmark of TDP-43 proteinopathies. Similarly, HIPK2-knockdown (KD) or expression of a kinase-dead mutant in neuronal SH-SY5Y and NSC-34 cells induces TDP-43 cytoplasmic delocalization without altering its expression levels. HIPK2 depletion changes TDP-43 interactome and results in the phosphorylation of TDP-43 RNA recognition motif 1 (RRM1), which is mediated by mitogen-activated protein kinase (MAPK) and known to interfere with TDP-43 binding to RNA. Interestingly, pharmacological inhibition of MAPK reverts the effects of HIPK2 depletion on TDP-43 subcellular localization. Altogether, these findings identify HIPK2 as a potential regulator of TDP-43 localization, providing new insights into the molecular mechanisms underlying ALS and related neurodegenerative disorders. Moreover, these results suggest that modulation of HIPK2 or its downstream signaling pathways could have important implications for the development of novel therapeutic strategies in TDP-43 proteinopathies.