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The JNK/c-Jun signaling axis contributes to the TDP-43-induced cell death

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Abstract

Dysregulation of transactive response DNA-binding protein-43 (TDP-43) is closely linked to the pathogenesis of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTLD-U). The contribution of the upregulation of TDP-43 expression to the pathogenesis has been strongly suggested by the observation that the level of TDP-43 expression is increased in both ALS and FTLD-U patients. We previously found that the low-grade (twice to five times more than the endogenous level) overexpression of TDP-43 induces neuronal cell death through the upregulation of Bim and CHOP expression and the downregulation of Bcl-xL expression. In this study, we further show that the low-grade overexpression of TDP-43 increases the level of phosphorylated c-Jun N-terminal kinase (JNK) and the co-incubation with a JNK inhibitor, the expression of a dominant-negative JNK, or the expression of a dominant-negative c-Jun inhibited the TDP-43-induced death in NSC34 motor neuronal cells. These data together suggest that the JNK/c-Jun signaling axis contributes to the TDP-43-induced cell death.

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Abbreviations

ALS:

Amyotrophic lateral sclerosis

Bim:

Bcl2-interacting mediator of cell death

CHOP:

C/EBP-homologous protein (growth arrest/DNA-damage inducible gene 153, GADD153)

FTLD-U:

Frontotemporal lobar degeneration with ubiquitin-positive inclusions

GAPDH:

Glyceraldehyde-3-phosphate dehydrogenase

JNK:

c-Jun N-terminal kinase

LDH:

Lactate dehydrogenase

TDP-43:

Transactive response DNA-binding protein-43

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Acknowledgments

We are especially grateful to Takako Hiraki for essential assistance throughout the study. We thank Dr. Jonathan Ham for providing adenovirus vectors and Dr. Neil Cashman for providing NSC34 cells. This work was supported in part by Grant-in-aid for Scientific Research (B) 20390072 and the ‘‘Promotion of Science and Technology’’ project for private universities with a matching fund subsidy from the Ministry of Education, Culture, Sports, Science, and Technology (MEXT) (to M.M.), and Grant-in-aid for Scientific Research Young Scientist (B) 22790261 and the Nakabayashi Trust for ALS research (to H. S.).

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Authors and Affiliations

  1. Department of Pharmacology, Tokyo Medical University, 6-1-1 Shinjuku, Shinjuku-ku, Tokyo, 160-8402, Japan

    Hiroaki Suzuki & Masaaki Matsuoka

  2. Research fellow of the Japan Society for the Promotion of Science, Tokyo, Japan

    Hiroaki Suzuki

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  1. Hiroaki Suzuki
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  2. Masaaki Matsuoka
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Correspondence to Masaaki Matsuoka.

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Suzuki, H., Matsuoka, M. The JNK/c-Jun signaling axis contributes to the TDP-43-induced cell death. Mol Cell Biochem 372, 241–248 (2013). https://doi.org/10.1007/s11010-012-1465-x

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  • DOI: https://doi.org/10.1007/s11010-012-1465-x

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