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Originally published In Press as doi:10.1074/mcp.M500090-MCP200 on June 20, 2005.
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Molecular & Cellular Proteomics 4:1849-1861, 2005.
© 2005 by The American Society for Biochemistry and Molecular Biology, Inc.

Research

Proteomic Analysis of Protein Expression and Oxidative Modification in R6/2 Transgenic Mice

A Model of Huntington Disease*

Marzia Perluigia,b, H. Fai Poonb, William Maragosc,d, William M. Piercee, Jon B. Kleinf, Vittorio Calabreseg, Chiara Cinia, Carlo De Marcoa and D. Allan Butterfieldb,h,i,j

From the aDepartment of Biochemical Sciences, University of Rome "La Sapienza," 00185 Rome, Italy, bDepartment of Chemistry, University of Kentucky, Lexington, Kentucky 40506-0055, cDepartment of Neurology, dAnatomy and Neurobiology, University of Kentucky, Lexington, Kentucky 40536-0305, eKidney Disease Program and Core Proteomics Laboratory and fDepartment of Pharmacology, University of Louisville School of Medicine and Veterans Affairs Medical Center, Louisville, Kentucky 40292, gDepartment of Chemistry, Section of Biochemistry, University of Catania, 95100 Catania, Italy, hCenter of Membrane Sciences, University of Kentucky, Lexington, Kentucky 40506-0059, and iSanders-Brown Center on Aging, University of Kentucky, Lexington, Kentucky 40536

Huntington disease (HD) is a hereditary neurodegenerative disorder characterized by motor, psychiatric, and cognitive symptoms. The genetic defect responsible for the onset of the disease, expansion of CAG repeats in exon 1 of the gene that codes for huntingtin on chromosome 4, has been unambiguously identified. On the other hand, the mechanisms by which the mutation causes the disease are not completely understood yet. However, defects in energy metabolism of affected cells may cause oxidative damage, which has been proposed as one of the underlying molecular mechanisms that participate in the etiology of the disease. In our effort to investigate the extent of oxidative damage occurring at the protein level, we used a parallel proteomic approach to identify proteins potentially involved in processes upstream or downstream of the disease-causing huntingtin in a well established HD mouse model (R6/2 transgenic mice). We have demonstrated that the expression levels of dihydrolipoamide S-succinyltransferase and aspartate aminotransferase increase consistently over the course of disease (10-week-old mice). In contrast, pyruvate dehydrogenase expression levels were found to be decreased in 10-week-old HD transgenic mice compared with young (4-week-old) mice. Our experimental approach also led to the identification of oxidatively modified proteins. Six proteins were found to be significantly oxidized in old R6/2 transgenic mice compared with either young transgenic mice or non-transgenic mice. These proteins are {alpha}-enolase, {gamma}-enolase (neuron-specific enolase), aconitase, the voltage-dependent anion channel 1, heat shock protein 90, and creatine kinase. Because oxidative damage has proved to play an important role in the pathogenesis and the progression of Huntington disease, our results for the first time identify specific oxidatively modified proteins that potentially contribute to the pathogenesis of Huntington disease.

jTo whom correspondence should be addressed: Dept. of Chemistry, Center of Membrane Sciences, and Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY 40506-0055. Tel.: 859-257-3184; Fax: 859-257-5876; E-mail: dabcns{at}uky.edu


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