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

Abstract

The mechanisms underlying detrimental effects of mutant huntingtin on striatal dysfunction in Huntingtons disease (HD) are not well understood. Although retinoic acid receptor beta (RAR{beta}) emerged recently as one of the top regulators of transcriptionally downregulated genes in the striatum of HD patients and mouse models of HD its involvement in disease progression remains elusive. We report that genetically compromised RAR{beta} signaling accelerates onset of motor abnormalities in R6/1 mouse model of HD. Transcriptional profiling revealed that downregulation of RAR{beta} expression in Rar{beta}+/-; R6/1 mice also accelerates transcriptional signature of disease progression by emergence of upregulated cluster of genes related to cell-cycle, stem cell maintenance and telencephalon development with concomitant downregulation of striatal cell-identity genes. The reactivation of proliferative activity demonstrated in the neurogenic niche and development-related transcriptional programs in the striatum prompt an attempt of lineage infidelity in HD striatum which may lead in consequence to disease-driving energy crisis as suggested by concomitant downregulation of transcripts essential for oxidative phosphorylation, a well-accepted correlate of HD physiopathology, and a metabolic change required for maintenance of proliferative activity and differentiation but not compatible with high energetic demand of differentiated and active neurons. HighlightsO_LICompromising RAR{beta} expression in R6/1 mouse model of HD accelerates onset of HD-like motor abnormalities C_LIO_LICompromised RAR{beta} signaling contributes to the progression of disease-related transcriptional changes in R6/1 mice C_LIO_LIRAR{beta} supports cell-identity maintenance in HD mouse model C_LI