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Estrogen-related receptor gamma regulates mitochondrial and synaptic genes and modulates vulnerability to synucleinopathy.
Fox, S N; McMeekin, L J; Savage, C H; Joyce, K L; Boas, S M; Simmons, M S; Farmer, C B; Ryan, J; Pereboeva, L; Becker, K; Auwerx, J; Sudarshan, S; Ma, J; Lee, A; Roberts, R C; Crossman, D K; Kralli, A; Cowell, R M.
Afiliación
  • Fox SN; Neuroscience Department, Drug Discovery Division, Southern Research, Birmingham, AL, 35205, USA.
  • McMeekin LJ; 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; 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.
  • Simmons MS; Neuroscience Department, Drug Discovery Division, Southern Research, Birmingham, AL, 35205, USA.
  • Farmer CB; Department of Cell, Developmental and Integrative Biology, University of Alabama at Birmingham, Birmingham, AL, 35294, USA.
  • Ryan J; Neuroscience Department, Drug Discovery Division, Southern Research, Birmingham, AL, 35205, USA.
  • Pereboeva L; Department of Cell, Developmental and Integrative Biology, University of Alabama at Birmingham, Birmingham, AL, 35294, USA.
  • Becker K; Department of Cell, Developmental and Integrative Biology, University of Alabama at Birmingham, Birmingham, AL, 35294, USA.
  • Auwerx J; Department of Psychiatry and Behavioral Neurobiology, University of Alabama at Birmingham, Birmingham, AL, 35294, USA.
  • Sudarshan S; NeuroInitiative, LLC, Jacksonville, FL, 32207, USA.
  • Ma J; Department of Pediatrics, Infectious Disease, Neuroscience Vector and Virus Core, University of Alabama at Birmingham, Birmingham, AL, 35223, USA.
  • Lee A; Department of Neurodegenerative Science, Van Andel Institute, Grand Rapids, MI, 49503, USA.
  • Roberts RC; Swiss Federal Institute of Technology Lausanne, Lausanne, Switzerland.
  • Crossman DK; Department of Urology, University of Alabama at Birmingham, Birmingham, AL, 35294, USA.
  • Kralli A; Department of Neurodegenerative Science, Van Andel Institute, Grand Rapids, MI, 49503, USA.
  • Cowell RM; NeuroInitiative, LLC, Jacksonville, FL, 32207, USA.
NPJ Parkinsons Dis ; 8(1): 106, 2022 Aug 18.
Article en En | MEDLINE | ID: mdl-35982091
ABSTRACT
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.

Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Tipo de estudio: Prognostic_studies Idioma: En Revista: NPJ Parkinsons Dis Año: 2022 Tipo del documento: Article País de afiliación: Estados Unidos

Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Tipo de estudio: Prognostic_studies Idioma: En Revista: NPJ Parkinsons Dis Año: 2022 Tipo del documento: Article País de afiliación: Estados Unidos