Endonuclease G mediates α-synuclein cytotoxicity during Parkinson's disease

• Sabrina Büttner ^[6] ; Lukas Habernig ^[1] ; Filomena Broeskamp ^[7] ; Doris Ruli ^[1] ; F Nora Vögtle ^[2] ; Manolis Vlachos ^[8] ; Francesca Macchi ^[3] ; Victoria Küttner ^[2] ; Didac Carmona-Gutierrez ^[1] ; Tobias Eisenberg ^[1] ; Julia Ring ^[1] ; Maria Markaki ^[8] ; Asli Aras Taskin ^[2] ; Stefan Benke ^[1] ; Christoph Ruckenstuhl ^[1] ; Ralf Braun ^[4] ; Chris Van den Haute ^[3] ; Tine Bammens ^[3] ; Anke van der Perren ^[3] ; Kai-Uwe Fröhlich ^[1] ; Joris Winderickx ^[3] ; Guido Kroemer ^[9] ; Veerle Baekelandt ^[3] ; Nektarios Tavernarakis ^[8] ; Gabor G Kovacs ^[5] ; Jörn Dengjel ^[2] ; Chris Meisinger ^[2] ; Stephan J Sigrist ^[7] ; Frank Madeo ^[1]
  1. [1] University of Graz

     University of Graz

     Graz, Austria

     
  2. [2] University of Freiburg

     University of Freiburg

     Stadtkreis Freiburg im Breisgau, Alemania

     
  3. [3] KU Leuven

     KU Leuven

     Arrondissement Leuven, Bélgica

     
  4. [4] University of Bayreuth

     University of Bayreuth

     Kreisfreie Stadt Bayreuth, Alemania

     
  5. [5] Medical University of Vienna

     Medical University of Vienna

     Innere Stadt, Austria

     
  6. [6] Institute of Molecular Biosciences, University of Graz, Graz, Austria; Institute for Biology/Genetics, Freie Universität Berlin, Berlin, Germany
  7. [7] Institute for Biology/Genetics, Freie Universität Berlin, Berlin, Germany
  8. [8] Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology-Hellas, Crete, Greece
  9. [9] 0INSERM, U848, Villejuif, France; 1Metabolomics Platform, Institut Gustave Roussy, Villejuif, France; 2Centre de Recherche des Cordeliers, Paris, France; 3Pôle de Biologie, Hôpital Européen Georges Pompidou, AP-HP, Paris, France; 4Université Paris Descartes, Sorbonne Paris Cité, Paris, France

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• Localización: EMBO journal: European Molecular Biology Organization, ISSN 0261-4189, Vol. 32, Nº. 23, 2013, págs. 3041-3054
• Idioma: inglés
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  • Malfunctioning of the protein α-synuclein is critically involved in the demise of dopaminergic neurons relevant to Parkinson's disease. Nonetheless, the precise mechanisms explaining this pathogenic neuronal cell death remain elusive. Endonuclease G (EndoG) is a mitochondrially localized nuclease that triggers DNA degradation and cell death upon translocation from mitochondria to the nucleus. Here, we show that EndoG displays cytotoxic nuclear localization in dopaminergic neurons of human Parkinson-diseased patients, while EndoG depletion largely reduces α-synuclein-induced cell death in human neuroblastoma cells. Xenogenic expression of human α-synuclein in yeast cells triggers mitochondria-nuclear translocation of EndoG and EndoG-mediated DNA degradation through a mechanism that requires a functional kynurenine pathway and the permeability transition pore. In nematodes and flies, EndoG is essential for the α-synuclein-driven degeneration of dopaminergic neurons. Moreover, the locomotion and survival of α-synuclein-expressing flies is compromised, but reinstalled by parallel depletion of EndoG. In sum, we unravel a phylogenetically conserved pathway that involves EndoG as a critical downstream executor of α-synuclein cytotoxicity.