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Molecular & Cellular Proteomics 8:720-734, 2009.
© 2009 by The American Society for Biochemistry and Molecular Biology, Inc.

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Research

A Large Number of Protein Expression Changes Occur Early in Life and Precede Phenotype Onset in a Mouse Model for Huntington Disease^*,S

Claus Zabel^,,¶, Lei Mao^,, Ben Woodman^||, Michael Rohe^**, Maik A. Wacker, Yvonne Kläre, Andrea Koppelstätter, Grit Nebrich, Oliver Klein, Susanne Grams, Andrew Strand, Ruth Luthi-Carter, Daniela Hartl, Joachim Klose and Gillian P. Bates^||

From the Institute for Human Genetics, Charité-Universitätsmedizin Berlin, 13353 Berlin, Germany, ^|| Department of Medical and Molecular Genetics, King's College London School of Medicine, Guy's Hospital London, London SE1 9RT, United Kingdom, ^** Molecular Cardiovascular Research, Max Delbrueck Center for Molecular Medicine, 13125 Berlin, Germany, Division of Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, and Laboratory of Functional Neurogenomics, Ecole Polytechnique Fédérale de Lausanne, 1015 Lausanne, Switzerland

Huntington disease (HD) is fatal in humans within 15–20 years of symptomatic disease. Although late stage HD has been studied extensively, protein expression changes that occur at the early stages of disease and during disease progression have not been reported. In this study, we used a large two-dimensional gel/mass spectrometry-based proteomics approach to investigate HD-induced protein expression alterations and their kinetics at very early stages and during the course of disease. The murine HD model R6/2 was investigated at 2, 4, 6, 8, and 12 weeks of age, corresponding to absence of disease and early, intermediate, and late stage HD. Unexpectedly the most HD stage-specific protein changes (71–100%) as well as a drastic alteration (almost 6% of the proteome) in protein expression occurred already as early as 2 weeks of age. Early changes included mainly the up-regulation of proteins involved in glycolysis/gluconeogenesis and the down-regulation of the actin cytoskeleton. This suggests a period of highly variable protein expression that precedes the onset of HD phenotypes. Although an up-regulation of glycolysis/gluconeogenesis-related protein alterations remained dominant during HD progression, late stage alterations at 12 weeks showed an up-regulation of proteins involved in proteasomal function. The early changes in HD coincide with a peak in protein alteration during normal mouse development at 2 weeks of age that may be responsible for these massive changes. Protein and mRNA data sets showed a large overlap on the level of affected pathways but not single proteins/mRNAs. Our observations suggest that HD is characterized by a highly dynamic disease pathology not represented by linear protein concentration alterations over the course of disease.

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