Downregulation of due to loss of TDP-43 function exacerbates motor neuron degeneration in amyotrophic lateral sclerosis.

TAR DNA-binding protein 43 (TDP-43) is of particular interest in the pathogenesis of amyotrophic lateral sclerosis (ALS). It has been speculated that loss of nuclear TDP-43 and its cytoplasmic aggregation contributes to neurodegeneration. Although considerable attention has been paid to RNA metabolism in TDP-43 function, TDP-43 is also known to act as a transcription factor. This study found that the expression of Nuclear-enriched abundant transcript 1 (), a long-non-coding RNA, was substantially downregulated in motor neurons with nuclear TDP-43 loss, but upregulated in those with preserved nuclear TDP-43, in the postmortem spinal cords of patients with sporadic ALS. TDP-43 depletion induced downregulation in Neuro2a cells, primary cortical neurons, and mouse spinal motor neurons. Furthermore, TDP-43 was found to positively regulate at the transcriptional level. Finally, knockout exacerbates neurodegeneration of hSOD1 mice accompanied by increased misfolded superoxide dismutase 1 (SOD1) aggregations. Transcriptome analysis revealed that knockout reduced protein folding-related genes, such as heat shock protein family A member 1A (), in the spinal cords of hSOD1 mice. Our results indicated that the loss of TDP-43 function enhances ALS neurodegeneration by losing the protective effect of .