Introduction: Current treatments for Huntington’s disease (HD) focus on reducing huntingtin protein (HTT) expression, but this may not suffice to address the cellular effects of HTT repeat expansion. Additional research is needed to explore neuroprotective strategies. Studies on transcriptional regulation show that the transcription factor ERR-gamma (ERRg; encoded by Esrrg) can modulate HD-related gene expression in spiny projection neurons (SPNs). Esrrg/ERRg overexpression in dopaminergic neurons enhances mitochondrial mass, boosts genes for respiration and autophagy, reduces synuclein inclusions, delays neuronal loss, and preserves axonal terminals in synucleinopathy models (relevant to Parkinson’s disease). These findings suggest that understanding ERRg’s roles in SPNs could inform potential therapeutic approaches in HD. 

Methods: In this study, we evaluated the influence of ERRg knockdown or overexpression on the expression of putative ERRg target genes in SPNs. One robust and reproducible response was for Egr1, an activity-dependent gene, which was reduced with ERRg overexpression and increased with ERRg deletion when measured by rt-PCR in homogenates of striatum. To determine whether the transcriptional changes were happening specifically in SPNs, tissues from both groups underwent small molecule fluorescence in situ hybridization (sm-FISH) protocols to amplify Egr1 in cells positive for Drd1 and Drd2 mRNA signal to define specific SPN populations. Cell Profiler software is utilized to automatically identify the amount of Egr1 expressed in either Drd1 or Drd2 cell types in confocal images. 

Results: While ERRg overexpression was capable of inducing subsets of genes involved in mitochondrial function and protein clearance, it caused a reduction in Egr1 expression. In contrast to overexpression, ERRg deletion caused an increase in Egr1.   

Conclusions: This finding could be explained by ERRg-mediated recruitment of transcriptional co-repressors to the promoter. Future experiments will explore the biology underlying the transcriptional effects of Esrrg/ERRg overexpression to determine whether ERRg activation could be neuroprotective in HD.