Affiliations: [a] Brain Disease Biomarker unit, Department of Experimental Medical Science, Wallenberg Neuroscience Centre, Lund University, Lund, Sweden | [b] Institute of Neurology, Department of Neurodegenerative Disease, UCL, London, UK | [c] Magnus Life Science, Rayne Building, 5 University Street, London, UK | [d] Faculty of Life Sciences, Michael Smith Building, Oxford Road, Manchester, M13 9PT, UK | [e] Victor Horsley Department of Neurosurgery, The National Hospital for Neurology and Neurosurgery, London, UK | [f] Reta Lila Weston Institute, UCL Institute of Neurology, London, UK
Correspondence to: Dr. Maria Björkqvist, Brain Disease Biomarker Unit, Department of Experimental Medical Science, Wallenberg Neuroscience Centre, BMC A10, Lund University, 221 84 Lund, Sweden. Tel.: +46 46 222 05 25; Fax: +46 46 222 05 31; E-mail: [email protected].
Abstract: Background:In addition to classical neurological symptoms, Huntington’s disease (HD) is complicated by peripheral pathology and both the mutant gene and the protein are found in cells and tissues throughout the body. Despite the adipose tissue gene expression alterations described in HD mouse models, adipose tissue and its gene expression signature have not been previously explored in human HD. Objective:We investigated gene expression signatures in subcutaneous adipose tissue obtained from control subjects, premanifest HD gene carriers and manifest HD subjects with the aim to identify gene expression changes and signalling pathway alterations in adipose tissue relevant to HD. Methods:Gene expression was assessed using Affymetrix GeneChip® Human Gene 1.0 ST Array. Target genes were technically validated using real-time quantitative PCR and the expression signature was validated in an independent subject cohort. Results:In subcutaneous adipose tissue, more than 500 genes were significantly different in premanifest HD subjects as compared to healthy controls. Pathway analysis suggests that the differentially expressed genes found here in HD adipose tissue are involved in fatty acid metabolism pathways, angiotensin signalling pathways and immune pathways. Transcription factor analysis highlights CREB1. Using RT-qPCR, we found that MAL2, AGTR2, COBL and the transcription factor CREB1 were significantly upregulated, with CREB1 and AGT also being significantly upregulated in a separate cohort. Conclusions:Distinct gene expression profiles can be seen in HD subcutaneous adipose tissue, with CREB1 highlighted as a key transcription factor.