Estrogen-related receptor gamma regulates mitochondrial and synaptic genes and modulates vulnerability to synucleinopathy

Many studies implicate mitochondrial dysfunction as a key contributor to cell loss in Parkinson disease (PD). Previous analyses of dopaminergic (DAergic) neurons from patients with Lewy-body pathology revealed a deficiency in nuclear-encoded genes for mitochondrial respiration, many of which are targets for the transcription factor estrogen-related receptor gamma (Esrrg/ERR gamma). We demonstrate that deletion of ERR gamma from DAergic neurons in adult mice was sufficient to cause a levodopa-responsive PD-like phenotype with reductions in mitochondrial gene expression and number, that partial deficiency of ERR gamma hastens synuclein-mediated toxicity, and that ERR gamma overexpression reduces inclusion load and delays synuclein-mediated cell loss. While ERR gamma deletion did not fully recapitulate the transcriptional alterations observed in postmortem tissue, it caused reductions in genes involved in synaptic and mitochondrial function and autophagy. Altogether, these experiments suggest that ERR gamma-deficient mice could provide a model for understanding the regulation of transcription in DAergic neurons and that amplifying ERR gamma-mediated transcriptional programs should be considered as a strategy to promote DAergic maintenance in PD.

Automated summary

ERR γ plays a crucial role in dopaminergic neurons and its deficiency is associated with reductions in mitochondrial function, synaptic genes, and autophagy-related genes, potentially serving as a model for PD.