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

Autor: Fox SN; Neuroscience Department, Drug Discovery Division, Southern Research, Birmingham, AL, 35205, USA.; Department of Cell, Developmental and Integrative Biology, University of Alabama at Birmingham, Birmingham, AL, 35294, USA., McMeekin LJ; Neuroscience Department, Drug Discovery Division, Southern Research, Birmingham, AL, 35205, USA.; Department of Cell, Developmental and Integrative Biology, University of Alabama at Birmingham, Birmingham, AL, 35294, USA., Savage CH; Neuroscience Department, Drug Discovery Division, Southern Research, Birmingham, AL, 35205, USA., Joyce KL; Neuroscience Department, Drug Discovery Division, Southern Research, Birmingham, AL, 35205, USA.; Department of Cell, Developmental and Integrative Biology, University of Alabama at Birmingham, Birmingham, AL, 35294, USA., Boas SM; Neuroscience Department, Drug Discovery Division, Southern Research, Birmingham, AL, 35205, USA.; Department of Cell, Developmental and Integrative Biology, University of Alabama at Birmingham, Birmingham, AL, 35294, USA., Simmons MS; Department of Cell, Developmental and Integrative Biology, University of Alabama at Birmingham, Birmingham, AL, 35294, USA., Farmer CB; Department of Psychiatry and Behavioral Neurobiology, University of Alabama at Birmingham, Birmingham, AL, 35294, USA., Ryan J; NeuroInitiative, LLC, Jacksonville, FL, 32207, USA., Pereboeva L; Department of Pediatrics, Infectious Disease, Neuroscience Vector and Virus Core, University of Alabama at Birmingham, Birmingham, AL, 35223, USA., Becker K; Department of Neurodegenerative Science, Van Andel Institute, Grand Rapids, MI, 49503, USA., Auwerx J; Swiss Federal Institute of Technology Lausanne, Lausanne, Switzerland., Sudarshan S; Department of Urology, University of Alabama at Birmingham, Birmingham, AL, 35294, USA., Ma J; Department of Neurodegenerative Science, Van Andel Institute, Grand Rapids, MI, 49503, USA., Lee A; NeuroInitiative, LLC, Jacksonville, FL, 32207, USA., Roberts RC; Department of Psychiatry and Behavioral Neurobiology, University of Alabama at Birmingham, Birmingham, AL, 35294, USA., Crossman DK; Department of Genetics, University of Alabama at Birmingham, Birmingham, AL, 35294, USA., Kralli A; Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA., Cowell RM; Neuroscience Department, Drug Discovery Division, Southern Research, Birmingham, AL, 35205, USA. rcowell@southernresearch.org.; Department of Cell, Developmental and Integrative Biology, University of Alabama at Birmingham, Birmingham, AL, 35294, USA. rcowell@southernresearch.org.
Jazyk: angličtina
Zdroj: NPJ Parkinson's disease [NPJ Parkinsons Dis] 2022 Aug 18; Vol. 8 (1), pp. 106. Date of Electronic Publication: 2022 Aug 18.
DOI: 10.1038/s41531-022-00369-w
Abstrakt: 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.
(© 2022. The Author(s).)
Databáze: MEDLINE
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