Proteomic analysis of 4-hydroxy-2-nonenal-modified proteins in G93A-SOD1 transgenic mice - A model of familial amyotrophic lateral sclerosis

Marzia Perluigi, H. Fai Poon, Kenneth Hensley, William M. Pierce, Jon B. Klein, Vittorio Calabrese, Carlo De Marco, D. Allan Butterfield

Research output: Contribution to journalArticlepeer-review

126 Scopus citations


Amyotrophic lateral sclerosis (ALS) is an age-related, fatal motor neuron degenerative disease occurring both sporadically (sALS) and heritably (fALS), with inherited cases accounting for approximately 10% of diagnoses. Although multiple mechanisms likely contribute to the pathogenesis of motor neuron injury in ALS, recent advances suggest that oxidative stress may play a significant role in the amplification, and possibly the initiation, of the disease. Lipid peroxidation is one of the several outcomes of oxidative stress. Since the central nervous system (CNS) is enriched with polyunsaturated fatty acids, it is particularly vulnerable to membrane-associated oxidative stress. Peroxidation of cellular membrane lipids or circulating lipoprotein molecules generates highly reactive aldehydes, among which is 4-hydroxy-2-nonenal (HNE). HNE levels are increased in spinal cord motor neurons of ALS patients, indicating that lipid peroxidation is associated with the motor neuron degeneration in ALS. In the present study, we used a parallel proteomic approach to identify HNE-modified proteins in the spinal cord tissue of a model of fALS, G93A-SOD1 transgenic mice, in comparison to the nontransgenic mice. We found three significantly HNE-modified proteins in the spinal cord of G93A-SOD1 transgenic mice: dihydropyrimidinase-related protein 2 (DRP-2), heat-shock protein 70 (Hsp70), and possibly α-enolase. These results support the role of oxidative stress as a major mechanism in the pathogenesis of ALS. Structural alteration and activity decline of functional proteins may consistently contribute to the neurodegeneration process in ALS.

Original languageEnglish
Pages (from-to)960-968
Number of pages9
JournalFree Radical Biology and Medicine
Issue number7
StatePublished - Apr 1 2005

Bibliographical note

Funding Information:
This work was supported in part by grants from NIH to D.A.B. [AG-05119; AG-10836] and to K.H. from Oklahoma Center for Advancement of Science and Technology [OCAST] HR02-149R; NIH [NS044154; and the ALS Association. The period spent by Dr. Marzia Perluigi in Prof. Butterfield's laboratory was supported by a post-doc grant of the University of Rome La Sapienza.


  • 4-Hydroxy-2-nonenal
  • Amyotrophic lateral sclerosis
  • Free radicals
  • Lipid peroxidation
  • Neurodegeneration
  • Oxidative stress

ASJC Scopus subject areas

  • Biochemistry
  • Physiology (medical)


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