TDP-43 associates with stalled ribosomes and contributes to cell survival during cellular stress

Authors

  • Shinji Higashi,

    Corresponding author
    1. Dementia Project, Department of Dementia and Higher Brain Function, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan
    • Department of Degenerative Neurological Diseases, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo, Japan
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  • Tomohiro Kabuta,

    1. Department of Degenerative Neurological Diseases, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo, Japan
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  • Yoshitaka Nagai,

    1. Department of Degenerative Neurological Diseases, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo, Japan
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  • Yukihiro Tsuchiya,

    1. Department of Degenerative Neurological Diseases, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo, Japan
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  • Haruhiko Akiyama,

    1. Dementia Project, Department of Dementia and Higher Brain Function, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan
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  • Keiji Wada

    1. Department of Degenerative Neurological Diseases, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo, Japan
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Address correspondence and reprint requests to Shinji Higashi, MD,PhD, Dementia Project, Department of Dementia and Higher Brain Function, Tokyo Metropolitan Institute of Medical Science, 2-1-6 Kamikitazawa, Setagaya-ku, Tokyo 156-0057, Japan. E-mail: higashi-sj@igakuken.or.jp

Abstract

TAR DNA-binding protein 43 (TDP-43) has emerged as an important contributor to amyotrophic lateral sclerosis and frontotemporal lobar degeneration. To understand the physiological roles of TDP-43 in the complex translational regulation mechanisms, we exposed cultured cells to oxidative stress induced by sodium arsenite (ARS) for different periods of time, leading to non-lethal or sublethal injury. Polysome profile analysis revealed that ARS-induced stress caused the association of TDP-43 with stalled ribosomes via binding to mRNA, which was not found under the steady-state condition. When the cells were exposed to short-term/non-lethal stress, TDP-43 associating with ribosomes localized to stress granules (SGs); this association was transient because it was immediately dissolved by the removal of the stress. In contrast, when the cells were exposed to long-term/sublethal stress, TDP-43 was excluded from SGs and shifted to the heavy fractions independent of any binding to mRNA. In these severely stressed cells, biochemical alterations of TDP-43, such as increased insolubility and disulfide bond formation, were irreversible. TDP-43 was finally phosphorylated via the ARS-induced c-jun N-terminal kinase pathway. In TDP-43-silenced cells, stalled mRNA and poly (A)+ RNA stability was disturbed and cytotoxicity increased under sublethal stress. Thus, TDP-43 associates with stalled ribosomes and contributes to cell survival during cellular stress.

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