Poly(ADP‐Ribose) Synthetase Activation: An Early Indicator of Neurotoxic DNA Damage

Jie Zhang, Andrew Pieper, Solomon H. Snyder

Research output: Contribution to journalArticlepeer-review

Abstract

Abstract: DNA damage activates a nuclear enzyme poly(ADP‐ribose) synthetase (PARS) that facilitates DNA repair by adding multiple ADP‐ribose groups to nuclear proteins such as histones and PARS itself. N‐Methyl‐d‐aspartate neurotoxicity may involve DNA damage excessively activating PARS to deplete its substrate NAD, as PARS inhibitors prevent this toxicity. We now show that PARS is rapidly and markedly activated in PC12 cells following treatment with neurotoxic agents, including the amyloid β‐protein, hydrogen peroxide, N‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP), and its active metabolite N‐methyl‐4‐phenylpyridine (MPP+). With MPP+, PARS activity is increased fivefold in 1 h and 20‐fold by 3 h. By contrast, direct measurement of DNA damage by the terminal‐deoxynucleotidyl transferase‐mediated dUTP‐biotin nick end‐labeling assay shows no significant increase by 3 h and less than fourfold by 24 h. These findings indicate that PARS activity can provide a simple, sensitive, and early index of DNA damage following neurotoxic insults.

Original languageEnglish (US)
Pages (from-to)1411-1414
Number of pages4
JournalJournal of Neurochemistry
Volume65
Issue number3
DOIs
StatePublished - Sep 1995

Keywords

  • Alzheimer's disease
  • Amyloid β‐protein
  • MPTP neurotoxicity
  • Parkinson's disease

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience

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