Högskolan i Skövde

Huntington’s disease (HD) is a fatal neurodegenerative disorder that is characterized by motor symptoms and non-motor features such as cognitive decline, psychiatric symptoms, progressive weight loss, metabolic alterations and changes in circadian rhythms. The non-motor features precede the motor symptoms by several years and are thought to be caused by a dysfunctional hypothalamus. Recent studies have shown that a high body mass index (BMI) was associated with slower disease progression, indicating that metabolic alterations may play an important role in clinical HD. Studies conducted on HD transgenic mouse models have shown that changes in body weight and metabolic phenotype are observed but at different age points. The aim of this study is to test the hypothesis that alterations in the same pool of metabolism regulating genes are common across different animal models of HD. Microarray experiments were carried out using hypothalamic RNA samples from 6 weeks old R6/2 mice, 2 months old BACHD mice and 4 weeks post injection adeno-associated viral vector (AAV) models. Gene expression was evaluated using the Affymetrix Mouse Gene 1.0 ST and Mouse Genome 430 version 2.0 chips. LIMMA analysis was performed to obtain the differentially expressed genes and pathway analysis using MetaCore^TM was performed to identify significantly altered pathways. The results showed that the top ten differentially expressed genes were enriched with hypothalamic factors and neuropeptides known to play a role in regulating metabolism such as histidine decarboxylase, vasopressin, CART and oxytocin. Orexin, tyrosine hydroxylase and L-dopa decarboxylase, were found to be enriched amongst the top twenty-five differentially expressed genes. Pathway analysis suggests that regulation of metabolism related pathways was significantly enriched in R6/2 models while pathways associated with development, differentiation and signal transduction were significantly enriched in AAV and BACHD models. Therefore, the analysis of gene expression changes in the hypothalamus of HD models may give new insights into the molecular mechanisms underlying the metabolic dysfunction in HD.