Analysis of transgenic mouse models of Huntington's disease

Huntington's disease (HD) is an autosomal dominant neurodegeneration, characterised by a movement disorder, complex cognitive disturbances and psychiatric problems. The disease is caused by the expansion of a CAG repeat in the HD gene on chromosome 4, giving rise to an expanded glutamine tract in the encoded protein, huntingtin. Microarray studies have already found substantial changes in gene expression in HD individuals and in transgenic mouse models of HD. However, it was important to determine whether a similar pattern of differential expression could be found at the protein level, in order to assess the significance of the observed gene expression changes to the disease process. For this, the Surface-Enhanced Laser Desorption Ionization-Time Of Flight (SELDI-TOF) system was used to analyse brain protein extracts from genetic mouse models of HD, both from whole brain and microdissected brain samples. Several brain regions and different timepoints of transgenic R6/1 and knock-in HdhQ92 and HdhQ150 mouse models were analysed. To analyse a wider range of the HD mouse brain proteome, HdhQ15 mouse caudate-putamen was analysed using the 2-D fluorescence Difference Gel Electrophoresis (DIGE) system. Differentially expressed proteins have been detected in brain samples from HD mice, and sixteen of these have been identified using Tandem Mass Spectrometry. Western blot analysis confirmed results for some of the proteins. The majority of the proteins identified as changed in expression had earlier been reported as changed in gene expression in human HD and mouse HD brain. In general, there is a high degree of agreement between the protein and the gene expression data. Some of the proteins identified in this study have been implicated in HD pathogenesis, and many are part of a pathogenic mechanism recognised to contribute to HD, such as mitochondrial dysfunction and deficient energy metabolism, oxidative stress and aberrant calcium signalling