Compromised retinoic acid receptor beta expression accelerates the onset of motor, cellular and molecular abnormalities in a mouse model of Huntington's disease.

The mechanisms underlying detrimental effects of mutant Huntingtin on striatal dysfunction in Huntington's disease (HD) are not well understood. Although retinoic acid receptor beta (RARβ) emerged recently as one of the top regulators of transcriptionally downregulated genes in the striatum of HD patients and mouse models, its involvement in disease progression remains elusive. Here we challenged functional relevance of RARβ dysregulation in HD onset and progression. Using a series of genetic mouse models, we investigated whether genetically reduced Rarβ expression synergizes with disease- causing mutant huntingtin (mHTT) fragment in R6/1 mice to accelerate HD-like behavioral, cellular and molecular striatal deregulations. We report that genetically compromised Rarβ signaling accelerates onset of motor abnormalities in the R6/1 HD mouse model. Transcriptional profiling revealed that downregulation of Rarβ expression in Rarβ+/-; R6/1 mice also accelerates transcriptional signature of disease progression and aging by emergence of a cluster of upregulated genes related to cell-cycle, stem cell maintenance and telencephalon development, contributing thereby to degradation of striatal cell-identity. Reactivation of proliferative activity in the neurogenic niche and development-related transcriptional programs in the striatum prompt an attempt of lineage infidelity in HD striatum which may lead as a consequence to disease-driving energy crisis, as suggested by downregulation of oxidative phosphorylation genes, a well-accepted correlate of HD physiopathology, and a metabolic condition required for maintenance of proliferative activity and differentiation but not compatible with high energetic demand of differentiated and active neurons. Overall, our data indicate that RARβ delays disease progression, perhaps by delaying aging process.