Estrogen-related receptor gamma regulates mitochondrial and synaptic genes and modulates vulnerability to synucleinopathy.
Stephanie N FoxL J McMeekinC H SavageK L JoyceS M BoasM S SimmonsC B FarmerJ RyanL PereboevaK BeckerJ AuwerxS SudarshanJ MaA LeeR C RobertsDavid K CrossmanA KralliRita M CowellPublished in: NPJ Parkinson's disease (2022)
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/ERRγ). We demonstrate that deletion of ERRγ 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 ERRγ hastens synuclein-mediated toxicity, and that ERRγ overexpression reduces inclusion load and delays synuclein-mediated cell loss. While ERRγ 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 ERRγ-deficient mice could provide a model for understanding the regulation of transcription in DAergic neurons and that amplifying ERRγ-mediated transcriptional programs should be considered as a strategy to promote DAergic maintenance in PD.
Keyphrases
- parkinson disease
- transcription factor
- gene expression
- oxidative stress
- deep brain stimulation
- single cell
- spinal cord
- genome wide identification
- cell therapy
- dna methylation
- genome wide
- climate change
- cell death
- signaling pathway
- dna binding
- estrogen receptor
- bone marrow
- heat shock
- replacement therapy
- adipose tissue
- bioinformatics analysis
- prefrontal cortex
- high fat diet induced
- genome wide analysis
- skeletal muscle