Downregulation of NEAT1 due to loss of TDP-43 function exacerbates motor neuron degeneration in amyotrophic lateral sclerosis.

1. Brain Commun. 2025 Jul 2;7(4):fcaf261. doi: 10.1093/braincomms/fcaf261. eCollection 2025. Downregulation of NEAT1 due to loss of TDP-43 function exacerbates motor neuron degeneration in amyotrophic lateral sclerosis. Kawakami Y(1), Iguchi Y(1), Li J(1), Amakusa Y(1), Yoshimura T(1), Chikuchi R(1), Yokoi S(1)(2), Iida M(1), Riku Y(1)(3), Iwasaki Y(3), Hirose T(4)(5), Nakagawa S(6), Katsuno M(1)(7). Author information: (1)Department of Neurology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, Aichi 466-8550, Japan. (2)Department of Pathophysiological Laboratory Sciences, Nagoya University Graduate School of Medicine, Nagoya, Aichi 466-8550, Japan. (3)Institute for Medical Science of Aging, Aichi Medical University, Nagakute, Aichi 480-1195, Japan. (4)Graduate School of Frontier Biosciences, Osaka University, Yamadaoka, Suita 565-0871, Japan. (5)Institute for Open and Transdisciplinary Research Initiatives, Osaka University, Yamadaoka, Suita 565-0871, Japan. (6)Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo 060-0808, Japan. (7)Department of Clinical Research Education, Nagoya University Graduate School of Medicine, Nagoya, Aichi 466-8550, Japan. 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 (NEAT1), 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 Neat1 downregulation in Neuro2a cells, primary corti