TAR DNA-binding protein of 43 kDa (TDP-43) is a DNA and RNA binding protein linked to neurodegenerative disorders and under pathological conditions accumulates in the cytoplasm. McGurk with Bonini and colleagues recently observed that inhibiting the Drosophila homologue of the poly(ADP-ribose) polymerases (PARPs) tankyrase 1 and tankyrase 2 (referred to here as Tnks-1/2) decreases the cytoplasmic accumulation of TDP-43 and associated neurotoxicity. In the current study, (McGurk et al., 2020), they now characterise the regulatory interaction between TDP-43 and Tnks-1/2 in mammalian cells. TDP-43 interacts with Tnks-1/2 through a newly identified tankyrase-binding domain (TBD). Although Tnks-1/2 activity is linked to proteasomal degradation, deletion of the TBD or inhibition of Tnks-1/2 leads to increased ubiquitylation and degradation of TDP-43, pointing to a function of Tnks-1/2 in stabilising TDP-43. The authors show that, although TDP-43 degradation occurs in the nucleus, Tnks-1/2 sequesters TDP-43 in the cytoplasm, impairing its turnover. Finally, they show that treatment with a small-molecule inhibitor of Tnks-1/2 protects against TDP-43-associated neurotoxicity in rat primary cortical neurons. This study thus identifies a new role for PARP enzymes in regulating the subcellular localization of proteins and uncovers Tnks-1/2 as a possible therapeutic target in neurodegenerative diseases.
