title: Modeling non-hereditary mechanisms of Alzheimer disease during apoptosis in yeast.
abstract: Impaired protein degradation and mitochondrial dysfunction are believed to contribute to neurodegenerative disorders, including Alzheimer disease (AD). In patients suffering from non-hereditary AD, UBB+1, the frameshift variant of ubiquitin B, accumulated in neurons affected by neurofibrillary tangles, which is a pathological hallmark. We established a yeast model expressing high levels of UBB+1, and could demonstrate that UBB+1interfered with both the ubiquitin-proteasome system (UPS) and mitochondrial function. More precisely, UBB+1promoted the mitochondrion-localized production of the basic amino acids arginine, ornithine, and lysine, which we identified as the decisive toxic event culminating in apoptosis. Inducing the UPS activity at mitochondria prevented the lethal basic amino acid accumulation and avoided UBB+1-triggered cell loss. The arginine/ornithine metabolism is altered in brains of AD patients, and VMS1, the mitochondrion-specific UPS component, co-existed with UBB+1in neurofibrillary tangles. Therefore, our data suggest that aberrant basic amino acid synthesis is a crucial link between UPS dysfunction and mitochondrial damage during AD progression.
authors.affiliation: Institute of Cell Biology, University of Bayreuth, 95440 Bayreuth, Germany.
authors.forename: Ralf J
authors.initials: RJ
authors.lastname: Braun
authors.affiliation: Institute of Molecular Biosciences, NAWI Graz, University of Graz, 8010 Graz, Austria. ; BioTechMed-Graz, 8010 Graz, Austria.
authors.forename: Cornelia
authors.initials: C
authors.lastname: Sommer
authors.affiliation: Institute of Cell Biology, University of Bayreuth, 95440 Bayreuth, Germany.
authors.forename: Christine
authors.initials: C
authors.lastname: Leibiger
authors.affiliation: Department of Neuroscience, Faculty of Health, Medicine and Life Sciences, Maastricht University, 6229 ER Maastricht, The Netherlands.
authors.forename: Romina J
authors.initials: RJ
authors.lastname: Gentier
authors.affiliation: FRIAS Freiburg Institute for Advanced Studies, Department of Dermatology, Medical Center, ZBSA Center for Biological Systems Analysis, BIOSS Centre for Biological Signalling Studies, University of Freiburg, 79104 Freiburg, Germany.
authors.forename: Verónica I
authors.initials: VI
authors.lastname: Dumit
authors.affiliation: Institute of Cell Biology, University of Bayreuth, 95440 Bayreuth, Germany.
authors.forename: Katrin
authors.initials: K
authors.lastname: Paduch
authors.affiliation: Institute of Molecular Biosciences, NAWI Graz, University of Graz, 8010 Graz, Austria.
authors.forename: Tobias
authors.initials: T
authors.lastname: Eisenberg
authors.affiliation: Institute of Molecular Biosciences, NAWI Graz, University of Graz, 8010 Graz, Austria.
authors.forename: Lukas
authors.initials: L
authors.lastname: Habernig
authors.affiliation: HEALTH Institute for Biomedicine and Health Sciences, Joanneum Research, 8010 Graz, Austria.
authors.forename: Gert
authors.initials: G
authors.lastname: Trausinger
authors.affiliation: HEALTH Institute for Biomedicine and Health Sciences, Joanneum Research, 8010 Graz, Austria.
authors.forename: Christoph
authors.initials: C
authors.lastname: Magnes
authors.affiliation: HEALTH Institute for Biomedicine and Health Sciences, Joanneum Research, 8010 Graz, Austria. ; Division of Endocrinology and Metabolism, Medical University of Graz, 8036 Graz, Austria.
authors.forename: Thomas
authors.initials: T
authors.lastname: Pieber
authors.affiliation: HEALTH Institute for Biomedicine and Health Sciences, Joanneum Research, 8010 Graz, Austria. ; Division of Endocrinology and Metabolism, Medical University of Graz, 8036 Graz, Austria.
authors.forename: Frank
authors.initials: F
authors.lastname: Sinner
authors.affiliation: FRIAS Freiburg Institute for Advanced Studies, Department of Dermatology, Medical Center, ZBSA Center for Biological Systems Analysis, BIOSS Centre for Biological Signalling Studies, University of Freiburg, 79104 Freiburg, Germany.
authors.forename: Jörn
authors.initials: J
authors.lastname: Dengjel
authors.affiliation: Department of Neuroscience, Faculty of Health, Medicine and Life Sciences, Maastricht University, 6229 ER Maastricht, The Netherlands.
authors.forename: Fred W V
authors.initials: FW
authors.lastname: Leeuwen
authors.affiliation: Apoptosis, Cancer & Immunity Laboratory, Team 11, Equipe labellisée Ligue contre le Cancer, INSERM Cordeliers Research Cancer, 75006 Paris, France. ; Institute of Cell Biology, University of Bayreuth, 95440 Bayreuth, Germany. ; Institute of Cell Biology, University of Bayreuth, 95440 Bayreuth, Germany. ; Institute of Cell Biology, University of Bayreuth, 95440 Bayreuth, Germany.
authors.forename: Guido
authors.initials: G
authors.lastname: Kroemer
authors.affiliation: Institute of Molecular Biosciences, NAWI Graz, University of Graz, 8010 Graz, Austria. ; BioTechMed-Graz, 8010 Graz, Austria.
authors.forename: Frank
authors.initials: F
authors.lastname: Madeo
keywords: aging; apoptosis; autophagy; cell death; microbes; microbial research; microbiome; neurodegeneration; unicellular organism