title: Redox proteomics analysis of oxidatively modified proteins in G93A-SOD1 transgenic mice--a model of familial amyotrophic lateral sclerosis.
abstract: Amyotrophic lateral sclerosis (ALS) is a fatal motor neuron degenerative disease characterized by the loss of neuronal function in the motor cortex, brain stem, and spinal cord. Familial ALS cases, accounting for 10-15% of all ALS disease, are caused by a gain-of-function mutation in Cu,Zn-superoxide dismutase (SOD1). Two hypotheses have been proposed to explain the toxic gain of function of mutant SOD (mSOD). One is that mSOD can directly promote reactive oxygen species and reactive nitrogen species generation, whereas the other hypothesis suggests that mSODs are prone to aggregation due to instability or association with other proteins. However, the hypotheses of oxidative stress and protein aggregation are not mutually exclusive. G93A-SOD1 transgenic mice show significantly increased protein carbonyl levels in their spinal cord from 2 to 4 months and eventually develop ALS-like motor neuron disease and die within 5-6 months. Here, we used a parallel proteomics approach to investigate the effect of the G93A-SOD1 mutation on protein oxidation in the spinal cord of G93A-SOD1 transgenic mice. Four proteins in the spinal cord of G93A-SOD1 transgenic mice have higher specific carbonyl levels compared to those of non-transgenic mice. These proteins are SOD1, translationally controlled tumor protein (TCTP), ubiquitin carboxyl-terminal hydrolase-L1 (UCH-L1), and, possibly, alphaB-crystallin. Because oxidative modification can lead to structural alteration and activity decline, our current study suggests that oxidative modification of UCH-L1, TCTP, SOD1, and possibly alphaB-crystallin may play an important role in the neurodegeneration of ALS.
authors.affiliation: Department of Chemistry, University of Kentucky, Lexington KY 40506, USA.
authors.forename: H Fai
authors.initials: HF
authors.lastname: Poon
authors.forename: Kenneth
authors.initials: K
authors.lastname: Hensley
authors.forename: Visith
authors.initials: V
authors.lastname: Thongboonkerd
authors.forename: Michael L
authors.initials: ML
authors.lastname: Merchant
authors.forename: Bert C
authors.initials: BC
authors.lastname: Lynn
authors.forename: William M
authors.initials: WM
authors.lastname: Pierce
authors.forename: Jon B
authors.initials: JB
authors.lastname: Klein
authors.forename: Vittorio
authors.initials: V
authors.lastname: Calabrese
authors.forename: D Allan
authors.initials: DA
authors.lastname: Butterfield
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000378:metabolism*; D000818:Animals; D014408:Biomarkers, Tumor / Q000378:metabolism; D015153:Blotting, Western; D004195:Disease Models, Animal; D015180:Electrophoresis, Gel, Two-Dimensional; D051379:Mice; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000378:metabolism; D010084:Oxidation-Reduction; D017354:Point Mutation; D040901:Proteomics; D013116:Spinal Cord / Q000378:metabolism; D013482:Superoxide Dismutase / Q000235:genetics*; D000090324:Tumor Protein, Translationally-Controlled 1; D043222:Ubiquitin Thiolesterase / Q000378:metabolism
chemical_list: D014408:Biomarkers, Tumor; D009419:Nerve Tissue Proteins; D013482:Superoxide Dismutase; D000090324:Tumor Protein, Translationally-Controlled 1; D043222:Ubiquitin Thiolesterase; C000715648:Tpt1 protein, mouse; C496976:Uchl1 protein, mouse