PARP-1 activation leads to cytosolic accumulation of TDP-43 in neurons.

Oxidative stress in neurodegenerative disease leads to poly(ADP-ribose) polymerase 1 (PARP-1) overactivation and subsequent cell death via excessive generation of Poly(ADP-ribose) polymer (PAR). PAR binds to neurodegenerative disease linked protein TAR DNA binding protein of 43 kDa (TDP-43). However, the consequence of this interaction is not yet fully understood. TDP-43 translocates from the nucleus to the cytoplasm in response to oxidative stress, but the mechanism of stress-induced translocation remains unknown. We used N-methyl-N-nitroso-N'-nitroguanidine (MNNG) and oxygen-glucose deprivation (OGD) in mouse neuronal cultures to activate PARP-1 and observed that pharmacological inhibition of PARP-1 blocked the cytosolic translocation of TDP-43. PARP-1 inhibition is also neuroprotective against both MNNG and OGD, suggesting that PARP inhibitors could play a role in the neuroprotective role in neurodegenerative diseases involving TDP-43. Together, these data present the novel finding that TDP-43 translocation depends on PARP-1 activation and set a ground for future research of how PARP-1 activation or PAR binding to TDP-43 may facilitate its cytosolic accumulation.