A large number of protein expression changes occur early in life and precede phenotype onset in a mouse model for huntington disease

Item Type:	Article
Title:	A large number of protein expression changes occur early in life and precede phenotype onset in a mouse model for huntington disease
Creators Name:	Zabel, C. and Mao, L. and Woodman, B. and Rohe, M. and Wacker, M.A. and Klaere, Y. and Koppelstaetter, A. and Nebrich, G. and Klein, O. and Grams, S. and Strand, A. and Luthi-Carter, R. and Hartl, D. and Klose, J. and Bates, G.P.
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.
Keywords:	Animal Disease Models, Disease Progression, Embryonic Development, Energy Metabolism, Gene Expression Regulation, Huntington Disease, Kinetics, Metabolic Networks and Pathways, Phenotype, Proteins, Messenger RNA, Time Factors, Tissue Extracts, Animals, Mice
Source:	Molecular & Cellular Proteomics
ISSN:	1535-9476
Publisher:	American Society for Biochemistry and Molecular Biology
Volume:	8
Number:	4
Page Range:	720-734
Date:	1 April 2009
Official Publication:	https://doi.org/10.1074/mcp.M800277-MCP200
PubMed:	View item in PubMed

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