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Disease-Associated Mutations of TDP-43 Promote Turnover of the Protein Through the Proteasomal Pathway

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Abstract

TAR DNA-binding protein (TDP-43) is a major component of most ubiquitin-positive neuronal and glial inclusions of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). A number of missense mutations in the TARDBP gene have been identified in patients with familial and sporadic ALS, as well as familial FTLD with ALS. In the diseased states, TDP-43 proteins exhibit characteristic alterations, including truncation, abnormal phosphorylation, and altered subcellular distribution. However, the mechanisms by which TDP-43 mutations induce neurodegeneration remain unclear at present. In the current study, we analyzed protein turnover and subcellular distribution of wild-type TDP-43 and two disease-associated mutants (G298S and A382T) in human neuroblastoma SH-SY5Y cells stably expressing TDP-43 with a C-terminal tag. Cycloheximide chase experiments revealed more rapid turnover of TDP-43 mutant proteins than their wild-type counterpart. The decrease in the TDP-43 level after cycloheximide treatment was partially recovered upon co-treatment with the proteasome inhibitor, epoxomicin, but not the lysosomotropic agent, chloroquine, suggesting involvement of the proteasomal pathway in TDP-43 degradation. Analysis of the subcellular distribution of TDP-43 revealed predominant localization in the nuclear fraction, whereas the relative level in the cytoplasm remained unaltered in cells expressing either mutant protein, compared with wild-type protein. Our results suggest that higher turnover of disease-associated mutant TDP-43 proteins through the ubiquitin proteasome system is pathogenetically relevant and highlight the significance of proteolysis in the pathogenetic mechanism of TDP-43 proteinopathy.

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Acknowledgments

We thank Dr. Yusuke Tozuka for assistance in immunocytochemistry and Drs. Akiko Oda and Ai Hosaka for technical assistance. This work was supported, in part, by grants from the Ministry of Health, Labour, and Welfare, Japan.

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The authors declare that they have no conflict of interest.

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  1. Kazumi Motoki

    Present address: Center for Multidisciplinary Brain Research, National Institute for Physiological Sciences, Myodaiji, Okazaki, 444-8585, Japan

Authors and Affiliations

  1. Department of Demyelinating Disease and Aging, National Institute of Neuroscience, NCNP, 4-1-1 Ogawahigashi, Kodaira, Tokyo, 187-8502, Japan

    Wataru Araki, Seiji Minegishi, Kazumi Motoki, Hideaki Kume & Yumiko M. Araki

  2. Department of Molecular Pharmacology, National Institute of Neuroscience, NCNP, Tokyo, 187-8502, Japan

    Hirohiko Hohjoh

  3. Department of Psychiatry and Behavioral Science, Graduate School of Medicine, Juntendo University, Tokyo, 113-8421, Japan

    Yumiko M. Araki

  4. Department of Neurology, Faculty of Medicine, University of Tsukuba, Ibaraki, 305-8575, Japan

    Akira Tamaoka

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Araki, W., Minegishi, S., Motoki, K. et al. Disease-Associated Mutations of TDP-43 Promote Turnover of the Protein Through the Proteasomal Pathway. Mol Neurobiol 50, 1049–1058 (2014). https://doi.org/10.1007/s12035-014-8644-6

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