title: Endonuclease G mediates α-synuclein cytotoxicity during Parkinson's disease.
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.
authors.affiliation: 1] Institute of Molecular Biosciences, University of Graz, Graz, Austria [2] Institute for Biology/Genetics, Freie Universität Berlin, Berlin, Germany.
authors.forename: Sabrina
authors.initials: S
authors.lastname: Büttner
authors.forename: Lukas
authors.initials: L
authors.lastname: Habernig
authors.forename: Filomena
authors.initials: F
authors.lastname: Broeskamp
authors.forename: Doris
authors.initials: D
authors.lastname: Ruli
authors.forename: F Nora
authors.initials: FN
authors.lastname: Vögtle
authors.forename: Manolis
authors.initials: M
authors.lastname: Vlachos
authors.forename: Francesca
authors.initials: F
authors.lastname: Macchi
authors.forename: Victoria
authors.initials: V
authors.lastname: Küttner
authors.forename: Didac
authors.initials: D
authors.lastname: Carmona-Gutierrez
authors.forename: Tobias
authors.initials: T
authors.lastname: Eisenberg
authors.forename: Julia
authors.initials: J
authors.lastname: Ring
authors.forename: Maria
authors.initials: M
authors.lastname: Markaki
authors.forename: Asli Aras
authors.initials: AA
authors.lastname: Taskin
authors.forename: Stefan
authors.initials: S
authors.lastname: Benke
authors.forename: Christoph
authors.initials: C
authors.lastname: Ruckenstuhl
authors.forename: Ralf
authors.initials: R
authors.lastname: Braun
authors.forename: Chris
authors.initials: C
authors.lastname: Van den Haute
authors.forename: Tine
authors.initials: T
authors.lastname: Bammens
authors.forename: Anke
authors.initials: A
authors.lastname: van der Perren
authors.forename: Kai-Uwe
authors.initials: KU
authors.lastname: Fröhlich
authors.forename: Joris
authors.initials: J
authors.lastname: Winderickx
authors.forename: Guido
authors.initials: G
authors.lastname: Kroemer
authors.forename: Veerle
authors.initials: V
authors.lastname: Baekelandt
authors.forename: Nektarios
authors.initials: N
authors.lastname: Tavernarakis
authors.forename: Gabor G
authors.initials: GG
authors.lastname: Kovacs
authors.forename: Jörn
authors.initials: J
authors.lastname: Dengjel
authors.forename: Chris
authors.initials: C
authors.lastname: Meisinger
authors.forename: Stephan J
authors.initials: SJ
authors.lastname: Sigrist
authors.forename: Frank
authors.initials: F
authors.lastname: Madeo
mesh_terms: D000368:Aged; D000818:Animals; D017209:Apoptosis; D017173:Caenorhabditis elegans / Q000254:growth & development / Q000378:metabolism; D004249:DNA Damage / Q000235:genetics; D004298:Dopamine / Q000494:pharmacology; D004331:Drosophila melanogaster / Q000254:growth & development / Q000378:metabolism; D004706:Endodeoxyribonucleases / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D015151:Immunoblotting; D007124:Immunoenzyme Techniques; D008928:Mitochondria / Q000378:metabolism / Q000473:pathology; D009447:Neuroblastoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D018384:Oxidative Stress; D010300:Parkinson Disease / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012441:Saccharomyces cerevisiae / Q000254:growth & development / Q000378:metabolism; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D013378:Substantia Nigra / Q000378:metabolism / Q000473:pathology*; D014407:Tumor Cells, Cultured; D051844:alpha-Synuclein / Q000235:genetics / Q000378:metabolism*
chemical_list: D012333:RNA, Messenger; D051844:alpha-Synuclein; D004706:Endodeoxyribonucleases; C052391:endonuclease G; D004298:Dopamine