Proteomic analysis of brain proteins in the gracile axonal dystrophy (gad) mouse, a syndrome that emanates from dysfunctional ubiquitin carboxyl-terminal hydrolase L-1, reveals oxidation of key proteins.
Ubiquitin carboxyl-terminal hydrolase L-1 (UCH L-1) is a crucial enzyme for proteasomal protein degradation that generates free monomeric ubiquitin. Our previous proteomic study identified UCH L-1 as one specific target of protein oxidation in Alzheimer's disease (AD) brain, establishing a link between the effect of oxidative stress on protein and the proteasomal dysfunction in AD. However, it is unclear how protein oxidation affects function, owing to the different responses of proteins to oxidation. Analysis of systems in which the oxidized protein displays lowered or null activity might be an excellent model for investigating the effect of the protein of interest in cellular metabolism and evaluating how the cell responds to the stress caused by oxidation of a specific protein. The gracile axonal dystrophy (gad) mouse is an autosomal recessive spontaneous mutant with a deletion on chromosome 5 within the gene encoding UCH L-1. The mouse displays axonal degeneration of the gracile tract. The aim of this proteomic study on gad mouse brain, with dysfunctional UCH L-1, was to determine differences in brain protein oxidation levels between control and gad samples. The results showed increased protein oxidation in thioredoxin peroxidase (peroxiredoxin), phosphoglycerate mutase, Rab GDP dissociation inhibitor alpha/ATP synthase and neurofilament-L in the gad mouse brain. These findings are discussed with reference to the effect of specific protein oxidation on potential mechanisms of neurodegeneration that pertain to the gad mouse.
Castegna
Alessandra
A
Department of Chemistry and Center of Membrane Sciences, University of Kentucky, Lexington, Kentucky 40506, USA.
Thongboonkerd
Visith
V
Klein
Jon
J
Lynn
Bert C
BC
Wang
Yu-Lai
YL
Osaka
Hitoshi
H
Wada
Keiji
K
Butterfield
D Allan
DA
D000818:Animals; D001923:Brain Chemistry; D002853:Chromatography, Liquid; D004195:Disease Models, Animal; D015180:Electrophoresis, Gel, Two-Dimensional; D020730:Guanine Nucleotide Dissociation Inhibitors / Q000032:analysis / Q000378:metabolism; D020271:Heredodegenerative Disorders, Nervous System / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008818:Mice, Neurologic Mutants; D016900:Neurofilament Proteins / Q000032:analysis / Q000378:metabolism; D010084:Oxidation-Reduction; D010544:Peroxidases / Q000032:analysis / Q000378:metabolism; D054464:Peroxiredoxins; D010736:Phosphoglycerate Mutase / Q000032:analysis / Q000378:metabolism; D011506:Proteins / Q000032:analysis* / Q000378:metabolism*; D040901:Proteomics; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D013577:Syndrome; D043222:Ubiquitin Thiolesterase / Q000172:deficiency* / Q000235:genetics
D020730:Guanine Nucleotide Dissociation Inhibitors; D016900:Neurofilament Proteins; D010544:Peroxidases; D054464:Peroxiredoxins; D010736:Phosphoglycerate Mutase; D011506:Proteins; D043222:Ubiquitin Thiolesterase; C086796:GDP dissociation inhibitor 1; C044882:neurofilament protein L; C496976:Uchl1 protein, mouse