title: A large number of protein expression changes occur early in life and precede phenotype onset in a mouse model for huntington disease.
abstract: 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.
authors.affiliation: Institute for Human Genetics, Charité-Universitätsmedizin Berlin, 13353 Berlin, Germany.
authors.forename: Claus
authors.initials: C
authors.lastname: Zabel
authors.forename: Lei
authors.initials: L
authors.lastname: Mao
authors.forename: Ben
authors.initials: B
authors.lastname: Woodman
authors.forename: Michael
authors.initials: M
authors.lastname: Rohe
authors.forename: Maik A
authors.initials: MA
authors.lastname: Wacker
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Kläre
authors.forename: Andrea
authors.initials: A
authors.lastname: Koppelstätter
authors.forename: Grit
authors.initials: G
authors.lastname: Nebrich
authors.forename: Oliver
authors.initials: O
authors.lastname: Klein
authors.forename: Susanne
authors.initials: S
authors.lastname: Grams
authors.forename: Andrew
authors.initials: A
authors.lastname: Strand
authors.forename: Ruth
authors.initials: R
authors.lastname: Luthi-Carter
authors.forename: Daniela
authors.initials: D
authors.lastname: Hartl
authors.forename: Joachim
authors.initials: J
authors.lastname: Klose
authors.forename: Gillian P
authors.initials: GP
authors.lastname: Bates
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D018450:Disease Progression; D047108:Embryonic Development; D004734:Energy Metabolism; D005260:Female; D005786:Gene Expression Regulation; D006816:Huntington Disease / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D007700:Kinetics; D008297:Male; D053858:Metabolic Networks and Pathways; D051379:Mice; D010641:Phenotype; D011506:Proteins / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D013997:Time Factors; D014020:Tissue Extracts
chemical_list: D011506:Proteins; D012333:RNA, Messenger; D014020:Tissue Extracts