Proteomic changes in the brains of Huntington's disease mouse models reflect pathology and implicate mitochondrial changes

Mouse models of Huntington's disease (HD) have been used extensively to recapitulate the pathological cascade of events in human HD. Mutant huntingtin interacts with many other proteins and has a well documented effect on gene expression. We were interested in whether changes in gene expression were translated into changes in the protein abundance in the brains of mouse models of HD. In two different HD knock in mouse models, the HdhQ150 and the HdhQ92, we detected changes in the abundance of proteins in mouse brain between wild-type and homozygous mutant animals. The numbers of changes detected rose with age and phenotypic severity. There were regional differences with most changes seen in the caudate and fewest in the cerebellum, reflecting the known pattern of gene expression changes in human HD and mouse models of HD and the known pathology. However, while some changes in the proteome followed changes in gene expression others did not directly reflect changes in gene expression seen in these animal models. Seven of the sixteen proteins detected have a known mitochondrial function, an enrichment of six-fold over that expected (p = 0.001): these mitochondrial proteins show both increases and decreases in abundance implying that a straightforward alteration in mitochondrial number is unlikely to account for this finding.