Abstract
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that selectively affects upper and lower motor neurons. TAR DNA-binding protein 43 kDa (TDP-43), an RNA-binding protein redistributes from nucleus to cytoplasm and forms aggregates, which are the histopathological hallmark of sporadic amyotrophic lateral sclerosis, in affected motor neurons. TDP-43 in the aberrant inclusion is known to be hyperphosphorylated at C-terminal sites, to be truncated at the N-terminal region, and to re- distribute from nucleus to cytoplasm or neurite. Ethacrynic acid (EA), which increases cellular oxidative stress through glutathione depletion, induces TDP-43C-terminal phosphorylation, insolubilization, C-terminal fragmentation, and cytoplasmic distribution in cultured neuronal cells and primary cortical neurons, suggesting that the loss of nuclear TDP-43 may play a role in the pathogenesis of ALS. Motor neuron- specific knock out of TDP- 43 results in progressive weight loss and motor impairment together with degeneration of large motor axon, grouped atrophy of the skeletal muscle, and denervation in the neuromuscular junction. These findings suggest that loss-of-function of TDP-43 appears to contribute to the pathogenesis of ALS.
