Neuronal TDP-43 regulates myelin formation via neurexin 1 mRNA stabilization
Abstract
Amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) develop as spatial pathologies in which neurons and glial cells are interconnected. TAR DNA-binding protein 43 (TDP-43) is a major pathological protein that is inextricably associated with ALS and FTLD. In this study, we investigated the roles of neuronal TDP-43 in neuron–oligodendrocyte interactions using neuron-specific TDP-43 knockout (TDP-43cKO) mice. TDP-43 depletion in neurons induced hypomyelination, which was confirmed by immunohistochemistry and ultrastructural analysis. In addition, conduction disturbance was revealed by electrophysiological analysis. The hypomyelination of TDP-43cKO mouse was restored by cytoplasmic TDP-43 supplementation in neurons. Neuron-specific transcriptome analysis revealed that neurexin 1 (NRXN1) is the regulatory target of TDP-43, which promotes myelin formation. The hypomyelination of TDP-43cKO mice was also restored by NRXN1b supplementation in neurons. We further confirmed that TDP-43 stabilizes Nrxn1 mRNA by binding to the Nrxn1 3’untranslated region (3’UTR). Although TDP-43cKO exhibited impaired recognition memory, the supplementation of NRXN1 in the hippocampus recovered the memory disturbances. In conclusion, this study demonstrates the neuron–oligodendrocyte interaction mediated by neuronal TDP-43 via NRXN1 mRNA stabilization. These findings shed light on neuron–oligodendrocyte interaction in the disease mechanisms of ALS/FTLD.
Article Details
Journal Info
Proceedings of the National Academy of Sciences
National Academy of Sciences
Authors (20)
Jiayi Li
Yohei Iguchi
Department of Neurology, Nagoya University Graduate School of Medicine
Kenji Yoshida
Department of Anatomy and Molecular Cell Biology, Nagoya University Graduate School of Medicine
Daisuke Kato
Kunihiko Araki
Department of Neurology, Nagoya University Graduate School of Medicine
Kenta Kobayashi
Section of Viral Vector Development, National Institute for Physiological Sciences
Satoshi Yokoi
Department of Pathophysiological Laboratory Sciences, Nagoya University Graduate School of Medicine
Rei Yoshimoto
Department of Applied Biological Sciences, Faculty of Agriculture, Setsunan University
Madoka Iida
Department of Neurology, Nagoya University Graduate School of Medicine
Yoshinobu Amakusa
Department of Neurology, Nagoya University Graduate School of Medicine
Yu Kawakami
Department of Neurology, Nagoya University Graduate School of Medicine
Takashi Yoshimura
Department of Neurology, Nagoya University Graduate School of Medicine
Ryo Chikuchi
Department of Neurology, Nagoya University Graduate School of Medicine
Koyo Tsujikawa
Department of Neurology, Nagoya University Graduate School of Medicine
Yuichi Riku
Department of Neurology, Nagoya University Graduate School of Medicine
Yasushi Iwasaki
Department of Neuropathology, Institute for Medical Science of Aging, Aichi Medical University
Yohei Okada
Department of Neural iPSC Research, Institute for Medical Science of Aging, Aichi Medical University
Nobuhiko Ohno
Division of Histology and Cell Biology, Department of Anatomy, Jichi Medical University
Hiroaki Wake
Masahisa Katsuno
Department of Neurology, Nagoya University Graduate School of Medicine