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Poly(ADP-ribosyl)ation of p53 contributes to TPEN-induced neuronal apoptosis

Hyun-Lim Kim1, Hana Ra1, Ki-Ryeong Kim1

  • 1Department of Molecular Biology, Sejong University, Seoul 143-747, Korea.

Molecules and Cells
|March 28, 2015
PubMed

Insights

Zinc depletion triggers neuronal apoptosis via p53. Poly(ADP-ribose) polymerase (PARP)-1 is essential for this process, regulating p53 stability and downstream apoptotic signaling in mouse cortical neurons.

Area of Science:

  • Neuroscience
  • Cell Biology
  • Biochemistry

Background:

  • Zinc depletion induces apoptosis in mouse cortical neurons through p53.
  • Poly(ADP-ribose) polymerase (PARP)-1 is a key enzyme in DNA repair and cell death pathways.

Purpose of the Study:

  • To investigate the role of PARP-1 in zinc depletion-induced neuronal apoptosis.
  • To determine if PARP-1 acts upstream of p53 in this apoptotic pathway.

Main Methods:

  • Using N,N,N',N'-tetrakis(2-pyridylmethyl) ethylenediamine (TPEN) to deplete intracellular zinc in cultured mouse cortical neurons.
  • Employing chemical PARP-1 inhibitors and genetic deletion of PARP-1.
  • Assessing p53 poly(ADP-ribosyl)ation, stability, and activity.
  • Measuring levels of proapoptotic proteins (PUMA, NOXA), cytochrome c release, and caspase-3 activation.

Main Results:

  • Chemical inhibition or genetic deletion of PARP-1 significantly reduced TPEN-induced neuronal apoptosis.
  • PARP-1 inhibition blocked p53 poly(ADP-ribosyl)ation, increased stability and activity induced by TPEN.
  • TPEN-induced upregulation of PUMA and NOXA was attenuated by PARP-1 inhibition.
  • PARP-1 inhibition prevented TPEN-induced cytochrome c release and caspase-3 activation.

Conclusions:

  • PARP-1 is essential for zinc depletion-induced apoptosis in mouse cortical neurons.
  • PARP-1 functions upstream of p53, mediating its activation and downstream effects.
  • Targeting PARP-1 may offer a therapeutic strategy for conditions involving zinc dysregulation and neuronal death.
Keywords:
NOXAPUMAcaspase-3p53poly(ADP-ribose) polymerase

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