ABSTRACT: Huntington disease (HD) is a fatal neurodegenerative disorder without cure, caused by an aberrant expansion of CAG repeats in the exon 1 of the Huntingtin (HTT) gene. Although the negative correlation between the number of CAG repeats and the age of disease onset is well established, additional factors may contribute to the high heterogeneity in the complex manifestation of the symptoms among patients. This variability is also observed in the phenotype of mouse models, even under controlled genetic and environmental conditions. To better understand this phenomenon, we analyzed the R6/1 strain in search of potential correlates between pathological motor/cognitive phenotypical traits and transcriptional alterations. HD-related genes (e.g., Penk, Plk5, Itpka), despite being downregulated across the examined brain areas (prefrontal cortex, striatum, hippocampus and cerebellum), exhibited a tissue-specific correlative association with particular phenotypical traits, attributable to the contribution of the brain region to regulate the trait (e.g., striatum and rotarod performance, cerebellum and feet clasping). Focusing on the striatum, we determined that the transcriptional dysregulation associated with HD was partially exacerbated in those mice showing poor phenotypical scores, affecting genes extensively described in this disease (e.g. Pde10a, Drd1, Drd2, Ppp1r1b). However, we also observed transcripts associated with relative better outcome, such as CCAAT-binding transcription factor NF-Y and others related with neuronal development, apoptosis and differentiation. In this study we demonstrate that altered brain transcription is capable of tracking the variations in the manifestation of HD-like symptoms in mouse models that may be extrapolated to the highly heterogeneous population of HD patients.
