Proteomic analysis of 4-hydroxy-2-nonenal-modified proteins in G93A-SOD1 transgenic mice--a model of familial amyotrophic lateral sclerosis.
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 alpha-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.
Perluigi
Marzia
M
Department of Biochemical Sciences, University of Rome La Sapienza, Rome 00185, Italy.
Fai Poon
H
H
Hensley
Kenneth
K
Pierce
William M
WM
Klein
Jon B
JB
Calabrese
Vittorio
V
De Marco
Carlo
C
Butterfield
D Allan
DA
D000447:Aldehydes / Q000032:analysis*; D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D004195:Disease Models, Animal; D018840:HSP70 Heat-Shock Proteins / Q000032:analysis* / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins; D015227:Lipid Peroxidation; D051379:Mice; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000032:analysis* / Q000378:metabolism; D018384:Oxidative Stress; D010751:Phosphopyruvate Hydratase / Q000032:analysis* / Q000378:metabolism; D040901:Proteomics; D013116:Spinal Cord / Q000737:chemistry* / Q000378:metabolism; D013482:Superoxide Dismutase / Q000235:genetics
D000447:Aldehydes; D018840:HSP70 Heat-Shock Proteins; D036341:Intercellular Signaling Peptides and Proteins; D009419:Nerve Tissue Proteins; C095114:collapsin response mediator protein-2; C109415:SOD1 G93A protein; D013482:Superoxide Dismutase; C457379:Eno1 protein, mouse; D010751:Phosphopyruvate Hydratase; C027576:4-hydroxy-2-nonenal