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Title: Endonuclease G mediates α-synuclein cytotoxicity during Parkinson's disease
Authors: Büttner, Sabrina ×
Habernig, Lukas
Broeskamp, Filomena
Ruli, Doris
Vögtle, Nora F
Vlachos, Manolis
Macchi, Francesca
Küttner, Victoria
Carmona-Gutierrez, Didac
Eisenberg, Tobias
Ring, Julia
Markaki, Maria
Taskin, Asli Aras
Benke, Stefan
Ruckenstuhl, Christoph
Braun, Ralf
Van Den Haute, Chris
Bammens, Tine
Van der Perren, Anke
Fröhlich, Kai-Uwe
Winderickx, Joris
Kroemer, Guido
Baekelandt, Veerle
Tavernarakis, Nektarios
Kovacs, Gabor
Dengjel, Jorn
Meisinger, Chris
Sigrist, Stephan J #
Madeo, Frank #
Issue Date: Oct-2013
Publisher: Nature Publishing Group
Series Title: EMBO Journal vol:32 issue:23 pages:3041-3054
Article number: 10.1038/emboj.2013.228
Abstract: 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.
URI: 
ISSN: 0261-4189
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Research Group for Neurobiology and Gene Therapy
Molecular Physiology of Plants and Micro-organisms Section - miscellaneous
× corresponding author
# (joint) last author

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