B15 Dysregulation of Gene Expression in the Striatum of Bachd Rats and Abnormalities Involved on Molecular and Protein Levels. (17th September 2014)

• Record Type: Journal Article
• Authors: Yu-Taeger, L; Bonin, M; Riess, O; Nguyen, HP
• Is Part Of: Journal of neurology, neurosurgery and psychiatry. Volume 85(2014)Supplement 1
• Page Start: A14
• Page End: A14
• Publication Date: 2014-09-17
• Subjects: BACHD rats -- gene expression -- striatum -- interaction -- chromatin structure -- huntingtin -- TBP; Neurology -- Periodicals; Nervous system -- Surgery -- Periodicals; Psychiatry -- Periodicals; 616.8
• DOI: 10.1136/jnnp-2014-309032.43
• Languages: English
• ISSNs: 0022-3050

Abstract

Abstract : Background: Huntington disease (HD) is an autosomal dominantly inherited neurodegenerative disorder caused by an expansion of CAG repeats in the gene coding for the huntingtin protein (htt). Mutant htt has been proposed to cause neuronal dysfunction and neuronal loss through multiple mechanisms. Transcriptional changes may be a core pathogenic feature of HD. Methods: Utilising 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, which carry full-length human mutant htt with different expression levels. Results: Applying a threshold of significance of 0.01, we found 1608 genes and 871 genes differently expressed in TG5 and TG9 rats compared to wild type littermates, respectively. We only chose highly up/down regulated genes for further analysis by setting an additional threshold of 1.5 for fold change. Comparison with data from human HD brains revealed a high concordance in involved functional and IPA (Ingenuity Pathway Analysis) canonical pathways relevant in HD. In addition, we investigated the causes leading to gene expression changes on molecular and protein levels in BACHD rats including the amount of wild type htt, interaction of mhtt with polyQ containing transcription factors as well as chromatin structure. Conclusions: Results of this study demonstrate that this BACHD rat model recapitulates accurately gene expression changes of the human disease and therefore supports its application in preclinical research. Analysis of causative events in BACHD rats confirmed some findings in in vitro test, and also provides a novel insight into initiators of perturbed gene transcription in HD.