Mutant TAR DNA-binding protein-43 induces oxidative injury in motor neuron-like cell.

Various missense mutations were identified in TAR DNA-binding protein-43 (TDP-43) in patients with amyotrophic lateral sclerosis (ALS). To explore the toxic effect of mutant TDP-43, we generated stable transfection of wild-type and mutant TDP-43 in motor neuron-like cell line. We found that mutant TDP-43 induced mitochondrial dysfunction, oxidative damage and nuclear accumulation of nuclear factor E2-related factor 2 (Nrf2). Nrf2 is an indicator and modulator of oxidative stress and is known to promote the expression of phase || detoxification enzyme including heme oxygenase-1 (HO-1). However, HO-1 was down regulated in cells expressing the mutant TDP-43, and could not be restored by sulforaphane which is a known stimulator of Nrf2 and phase || detoxification enzyme, including HO-1. Nevertheless, sulforaphane reduced the level of lactate dehydrogenase and lipoperoxidation products in cells expressing TDP-43 mutant. However, sulforaphane could upregulate the expression of HO-1 and NAD(P)H/quinone oxidoreductase-1 (NQO-1) in cells transfected with the empty vector and the wild-type TDP-43. Thus, sulforaphane protected cells against mutant TDP-43 independent of Nrf2-antioxidant response element (ARE) pathway. How mutant TDP-43 reduces expression of HO-1 and prevents sulforaphane from activating Nrf2 signaling remains to be investigated.