title: Accumulation of Basic Amino Acids at Mitochondria Dictates the Cytotoxicity of Aberrant Ubiquitin.
abstract: Neuronal accumulation of UBB+1, a frameshift variant of ubiquitin B, is a hallmark of Alzheimer's disease (AD). How UBB+1contributes to neuronal dysfunction remains elusive. Here, we show that in brain regions of AD patients with neurofibrillary tangles UBB+1co-exists with VMS1, the mitochondrion-specific component of the ubiquitin-proteasome system (UPS). Expression of UBB+1in yeast disturbs the UPS, leading to mitochondrial stress and apoptosis. Inhibiting UPS activity exacerbates while stimulating UPS by the transcription activator Rpn4 reduces UBB+1-triggered cytotoxicity. High levels of the Rpn4 target protein Cdc48 and its cofactor Vms1 are sufficient to relieve programmed cell death. We identified the UBB+1-induced enhancement of the basic amino acids arginine, ornithine, and lysine at mitochondria as a decisive toxic event, which can be reversed by Cdc48/Vms1-mediated proteolysis. The fact that AD-induced cellular dysfunctions can be avoided by UPS activity at mitochondria has potentially far-reaching pathophysiological implications.
authors.affiliation: Institute of Cell Biology, University of Bayreuth, 95440 Bayreuth, Germany. Electronic address: ralf.braun@uni-bayreuth.de.
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 G
authors.initials: RJG
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
authors.initials: FW
authors.lastname: van Leeuwen
authors.affiliation: Apoptosis, Cancer and Immunity Laboratory, Team 11, Equipe labellisée Ligue contre le Cancer, INSERM Cordeliers Research Cancer, 75006 Paris, France; Cell Biology and Metabolomics Platforms, Gustave Roussy Comprehensive Cancer Center, 94805 Villejuif, France; Pôle de Biologie, Hôpital Européen Georges Pompidou, AP-HP, 75015 Paris, France; Université Paris Descartes, Sorbonne Paris Cité, 75005 Paris, France.
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. Electronic address: frank.madeo@uni-graz.at.
authors.forename: Frank
authors.initials: F
authors.lastname: Madeo