4-Hydroxynonenal oxidatively modifies histones: Implications for Alzheimer's disease

Jennifer Drake, Robin Petroze, Alessandra Castegna, Qunxing Ding, Jeffrey N. Keller, William R. Markesbery, Mark A. Lovell, D. Allan Butterfield

Research output: Contribution to journalArticlepeer-review

63 Scopus citations

Abstract

There is increasing evidence of DNA oxidation and altered DNA repair mechanisms in Alzheimer's disease (AD) brain. Histones, which interact with DNA, conceivably could provide a protective shield for DNA against oxidative stress. However, because of their abundant lysine residues, histones may be a target for 4-hydroxynonenal (HNE) modification. In this study, we have shown that HNE binds to histones and that this binding affects the conformation of the histone, measured by electron paramagnetic resonance in conjunction with a protein-specific spin label. The covalent modification to the histone by HNE affects the ability of the histone to bind DNA. Interestingly, acetylated histones appear to be more susceptible to HNE modifications than control histones. Conceivably, altered DNA-histone interactions, subsequent to oxidative modification of histones by the lipid peroxidation product HNE, may contribute to the vulnerability of DNA to oxidation in AD brain.

Original languageEnglish
Pages (from-to)155-158
Number of pages4
JournalNeuroscience Letters
Volume356
Issue number3
DOIs
StatePublished - Feb 19 2004

Bibliographical note

Funding Information:
This research was supported in part by NIH grants AG05119 and AG10836 to DAB, NIH grant 5P50AG05114 and a grant from the Abercombie Foundation to WRM, and NIH grants AG018437 and AG05119 and an American Heart Association grant to JNK.

Keywords

  • Alzheimer's disease
  • DNA oxidation
  • Histone-DNA interactions
  • Protein conformation
  • Spin labeling

ASJC Scopus subject areas

  • Neuroscience (all)

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