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

Hiroaki Suzuki1, Masaaki Matsuoka

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

Molecular and Cellular Biochemistry
|September 25, 2012
PubMed

Insights

Transactive response DNA-binding protein-43 (TDP-43) overexpression triggers neuronal death in neurodegenerative diseases. This study reveals the JNK/c-Jun signaling pathway is crucial for TDP-43-induced cell death.

Area of Science:

  • Neuroscience
  • Molecular Biology
  • Cell Biology

Background:

  • Dysregulation of transactive response DNA-binding protein-43 (TDP-43) is implicated in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD).
  • Increased TDP-43 expression levels are observed in ALS and FTLD-U patients, suggesting its upregulation contributes to pathogenesis.
  • Previous research indicated that low-grade TDP-43 overexpression induces neuronal cell death via specific gene expression changes.

Purpose of the Study:

  • To investigate the role of the JNK/c-Jun signaling pathway in TDP-43-induced neuronal cell death.
  • To elucidate the molecular mechanisms underlying TDP-43-mediated neurotoxicity.

Main Methods:

  • Utilizing NSC34 motor neuronal cells.
  • Inducing low-grade overexpression of TDP-43.
  • Assessing levels of phosphorylated c-Jun N-terminal kinase (JNK).
  • Employing JNK inhibitors, dominant-negative JNK, and dominant-negative c-Jun expression.

Main Results:

  • Low-grade TDP-43 overexpression led to increased levels of phosphorylated JNK.
  • Inhibition of JNK signaling (using inhibitors or dominant-negative constructs) significantly reduced TDP-43-induced cell death.
  • Expression of dominant-negative c-Jun also protected against TDP-43-induced neuronal death.

Conclusions:

  • The JNK/c-Jun signaling axis plays a critical role in mediating neuronal cell death induced by TDP-43 overexpression.
  • Targeting the JNK/c-Jun pathway may offer a therapeutic strategy for neurodegenerative diseases associated with TDP-43.
  • These findings deepen our understanding of TDP-43's contribution to ALS and FTLD pathogenesis.

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