Dysregulation of gene expression in the striatum of BACHD rats expressing full-length mutant huntingtin and associated abnormalities on molecular and protein levels.
Huntington disease (HD) is an autosomal dominantly inherited neurodegenerative disorder caused by a CAG repeat expansion in the gene coding for the huntingtin protein (HTT). Mutant HTT (mHTT) has been proposed to cause neuronal dysfunction and neuronal loss through multiple mechanisms. Transcriptional changes may be a core pathogenic feature of HD. Utilizing the Affymetrix platform we performed a genome-wide RNA expression analysis in two BACHD transgenic rat lines (TG5 and TG9) at 12 months of age, both of which carry full-length human mHTT but with different expression levels. By defining the threshold of significance at p < 0.01, we found 1608 genes and 871 genes differentially expressed in both TG5 and TG9 rats when compared to the wild type littermates, respectively. We only chose the highly up-/down-regulated genes for further analysis by setting an additional threshold of 1.5 fold change. Comparing gene expression profiles of human HD brains and BACHD rats revealed a high concordance in both functional and IPA (Ingenuity Pathway Analysis) canonical pathways relevant to HD. In addition, we investigated the causes leading to gene expression changes at molecular and protein levels in BACHD rats including the involvement of polyQ-containing transcription factors TATA box-binding protein (TBP), Sp1 and CBP as well as the chromatin structure. We demonstrate that the BACHD rat model recapitulates the gene expression changes of the human disease supporting its role as a preclinical research animal model. We also show for the first time that TFIID complex formation is reduced, while soluble TBP is increased in an HD model. This finding suggests that mHTT is a competitor instead of a recruiter of polyQ-containing transcription factors in the transcription process in HD.
Institute of Medical Genetics and Applied Genomics, University of Tuebingen, Calwerstrasse 7, 72076 Tuebingen, Germany; Centre for Rare Diseases, University of Tuebingen, Calwerstrasse 7, 72076 Tuebingen, Germany.
Libo
L
Yu-Taeger
Institute of Medical Genetics and Applied Genomics, University of Tuebingen, Calwerstrasse 7, 72076 Tuebingen, Germany; Centre for Rare Diseases, University of Tuebingen, Calwerstrasse 7, 72076 Tuebingen, Germany.
Michael
M
Bonin
Institute of Medical Genetics and Applied Genomics, University of Tuebingen, Calwerstrasse 7, 72076 Tuebingen, Germany; Centre for Rare Diseases, University of Tuebingen, Calwerstrasse 7, 72076 Tuebingen, Germany.
Janice
J
Stricker-Shaver
Institute of Medical Genetics and Applied Genomics, University of Tuebingen, Calwerstrasse 7, 72076 Tuebingen, Germany; Centre for Rare Diseases, University of Tuebingen, Calwerstrasse 7, 72076 Tuebingen, Germany.
Olaf
O
Riess
Institute of Medical Genetics and Applied Genomics, University of Tuebingen, Calwerstrasse 7, 72076 Tuebingen, Germany; Centre for Rare Diseases, University of Tuebingen, Calwerstrasse 7, 72076 Tuebingen, Germany. Electronic address: hoa.nguyen@med.uni-tuebingen.de.
Hoa Huu Phuc
HHP
Nguyen
D000818:Animals; D002843:Chromatin / Q000378:metabolism; D003342:Corpus Striatum / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D004587:Electrophoresis, Agar Gel; D015870:Gene Expression; D020869:Gene Expression Profiling; D006801:Humans; D000071058:Huntingtin Protein / Q000235:genetics* / Q000378:metabolism*; D015151:Immunoblotting; D007150:Immunohistochemistry; D046228:Microarray Analysis; D009154:Mutation; D017207:Rats, Sprague-Dawley; D055647:Rats, Transgenic; D060888:Real-Time Polymerase Chain Reaction; D035181:TATA-Box Binding Protein / Q000378:metabolism
D002843:Chromatin; C086055:HTT protein, human; D000071058:Huntingtin Protein; D035181:TATA-Box Binding Protein
BACHD rats; Gene expression; Huntington disease; Striatum