Transcriptional correlates of the pathological phenotype in a Huntington\u2019s disease mouse model

Andrea Gallardo-Orihuela,Irati Hervás-Corpión,Francisco Mora-López,Carmen Hierro-Bujalance,Monica Garcia-Alloza,Luis M Valor,Antonio Campos-Caro,Gema Jiménez-Gómez,Daniel Sanchez-Sotano

doi:10.1038/s41598-019-55177-9

Abstract

Huntington disease (HD) is a fatal neurodegenerative disorder without a cure that is caused by an aberrant expansion of CAG repeats in exon 1 of the huntingtin (HTT) gene. Although a negative correlation between the number of CAG repeats and the age of disease onset is established, additional factors may contribute to the high heterogeneity of the complex manifestation of symptoms among patients. This variability is also observed in mouse models, even under controlled genetic and environmental conditions. To better understand this phenomenon, we analysed 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 (the prefrontal cortex, striatum, hippocampus and cerebellum), exhibited tissue-specific correlations with particular phenotypical traits that were attributable to the contribution of the brain region to that 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 mice that showed poor overall phenotypical scores, especially in genes with relevant roles in striatal functioning (e.g., Pde10a, Drd1, Drd2, Ppp1r1b). However, we also observed transcripts associated with relatively better outcomes, such as Nfya (CCAAT-binding transcription factor NF-Y subunit A) plus others related to neuronal development, apoptosis and differentiation. In this study, we demonstrated that altered brain transcription can be related to the manifestation of HD-like symptoms in mouse models and that this can be extrapolated to the highly heterogeneous population of HD patients.

Highlights

Huntington disease (HD) is a fatal neurodegenerative disorder without a cure that is caused by an aberrant expansion of CAG repeats in exon 1 of the huntingtin (HTT) gene
In the Morris water maze task, mutant mice did not show differences compared to their wild-type littermates (Fig. 1B–D), but cognitive impairment was more evident in the novel object discrimination (NOD) task, in which mutant mice were highly inefficient at remembering familiar objects and both spatial and temporal changes (Fig. 1E)
We found that the level of transcriptional dysregulation of certain genes can be associated to the degree of impairment for specific phenotypical traits in the R6/1 strain, without a profound influence of the number of CAG repeats and mutant HTT fragment (mHtt) transgene expression in defining the interindividual variability in the mice of our study

Summary

Introduction

Huntington disease (HD) is a fatal neurodegenerative disorder without a cure that is caused by an aberrant expansion of CAG repeats in exon 1 of the huntingtin (HTT) gene. A negative correlation between the number of CAG repeats and the age of disease onset is established, additional factors may contribute to the high heterogeneity of the complex manifestation of symptoms among patients This variability is observed in mouse models, even under controlled genetic and environmental conditions. To improve and personalize clinical counseling, there is a need for valuable biomarkers to monitor the health status of individuals, assess the dosing, efficacy and safety of potential therapeutic approaches and minimize uncertainty in clinical decision-making This is especially relevant in HD, as there is increasing evidence of a long-lasting presymptomatic stage with underlying pathological processes[2]; the number of CAG repeats, inversely correlated with the age of disease onset[3,4], is unable to explain the progression and manifestation of certain symptoms[5,6,7]. We describe that even slight transcriptional and phenotypical variations can show certain associations in a tissue-dependent manner in environmentally and genetically controlled R6/1 mice

Methods

Results

Conclusion