Novel proteomic changes in brain mitochondria provide insights into mitochondrial dysfunction in mouse models of...

Huntington's disease (HD) is a progressive ultimately fatal disorder caused by a glutamine-encoding CAG expansion in the huntingtin (HTT) gene that results in degeneration mainly in striatal and cerebro-cortical brain regions. Mitochondrial dysfunction is one important facet of HD pathogenesis. Here we used R6/2 and YAC128 HD mouse models of human HD, that express different HTT transgenes and have different progression rates, to identify HD brain mitochondrial proteomic signatures. Cerebral cortical mitochondrial preparations from HD and wild-type litter mate mice were compared by two-dimensional SDS-PAGE electrophoresis and MALDI-TOF/TOF mass spectrometry. Proteomic analyses inferred 17 and 12 differentially expressed proteins, respectively in 12 week R6/2 and 15 month YAC128 HD mice, compared to controls. Peroxiredoxin 3, stress-70, DJ-1, isocitrate dehydrogenase [NAD] α subunit and ATP synthase subunit D were differentially expressed in both models. Using the PANTHER (Protein ANalysis THrough Evolutionary Relationships) classification system we show that the inferred proteins are involved in oxidative stress defense, oxidative phosphorylation, the citric acid cycle, pyruvate metabolism, apoptosis, protein folding and iron metabolism. Common mitochondrial proteomic changes are significant in mouse models of middle (YAC128) and advanced (R6/2) HD despite differences in the HTT transgenes, age, genetic background and disease stage. The findings identify a proteomic signature of HD mitochondria in mouse models that includes previously unrecognized proteins.