biostudies-literatureMcGurk LTarget ALSGlenn Foundation for Medical ResearchNINDS NIH HHSNational Institutes of HealthAcademy of Medical Sciencesjcs245811https://www.ebi.ac.uk/biostudies/studies/S-EPMC7328137biostudies-literatureUnknown133(12)In >95% of cases of amyotrophic lateral sclerosis (ALS) and ∼45% of frontotemporal degeneration (FTD), the RNA/DNA-binding protein TDP-43 is cleared from the nucleus and abnormally accumulates in the cytoplasm of affected brain cells. Although the cellular triggers of disease pathology remain enigmatic, mounting evidence implicates the poly(ADP-ribose) polymerases (PARPs) in TDP-43 neurotoxicity. Here we show that inhibition of the PARP enzymes tankyrase 1 and tankyrase 2 (referred to as Tnks-1/2) protect primary rodent neurons from TDP-43-associated neurotoxicity. We demonstrate that Tnks-1/2 interacts with TDP-43 via a newly defined tankyrase-binding domain. Upon investigating the functional effect, we find that interaction with Tnks-1/2 inhibits the ubiquitination and proteasomal turnovJournal of cell scienceTDP-43, a protein central to amyotrophic lateral sclerosis, is destabilized by tankyrase-1 and -2.PMC7328137SBF005\10805R01NS073660R01 NS073660R35 NS097275R35NS097275Rifai OMBonini NMMcGurk LfalseTDP-43, a protein central to amyotrophic lateral sclerosis, is destabilized by tankyrase-1 and -2.In >95% of cases of amyotrophic lateral sclerosis (ALS) and ∼45% of frontotemporal degeneration (FTD), the RNA/DNA-binding protein TDP-43 is cleared from the nucleus and abnormally accumulates in the cytoplasm of affected brain cells. Although the cellular triggers of disease pathology remain enigmatic, mounting evidence implicates the poly(ADP-ribose) polymerases (PARPs) in TDP-43 neurotoxicity. Here we show that inhibition of the PARP enzymes tankyrase 1 and tankyrase 2 (referred to as Tnks-1/2) protect primary rodent neurons from TDP-43-associated neurotoxicity. We demonstrate that Tnks-1/2 interacts with TDP-43 via a newly defined tankyrase-binding domain. Upon investigating the functional effect, we find that interaction with Tnks-1/2 inhibits the ubiquitination and proteasomal turnov2020-01-01T00:00:00Z2020 Jun2026-05-09T03:26:37.799Z2020-11-07T11:33:19ZS-EPMC73281373240956510.1242/jcs.245811