Modeling non-hereditary mechanisms of Alzheimer disease during apoptosis in yeast

Microbial Cell

Guido Kroemer¹  Romina J.G. Gentier²  Fred W. van Leeuwen²  Jörn Dengjel³  Verónica I. Dumit³  Christoph Magnes⁴  Thomas Pieber⁴  Gert Trausinger⁴  Frank Sinner⁴  Christine Leibiger⁵  Katrin Paduch⁵  Ralf J. Braun⁵  Frank Madeo⁶  Tobias Eisenberg⁶  Cornelia Sommer⁶  Lukas Habernig⁶ 

[1] Apoptosis, Cancer and Immunity Laboratory, Team 11, Equipe labellisée Ligue contre le Cancer, INSERM Cordeliers Research Cancer, 75006 Paris, France.;Department of Neuroscience, Faculty of Health, Medicine and Life Sciences, Maastricht University, 6229 ER Maastricht, The Netherlands.;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.;HEALTH Institute for Biomedicine and Health Sciences, Joanneum Research, 8010 Graz, Austria.;Institute of Cell Biology, University of Bayreuth, 95440 Bayreuth, Germany.;Institute of Molecular Biosciences, NAWI Graz, University of Graz, 8010 Graz, Austria.;

关键词: Alzheimer’s disease;    ubiquitin;    proteasome;    UBB+1;    Cdc48;    Vms1;    ANKZF1;    ZNF744;    mitochondria;    basic amino acids;    arginine;    ornithine;    lysine;    Saccharomyces cerevisiae;    apoptosis;    necrosis;    programmed cell death;   

DOI  :  10.15698/mic2015.04.199

来源: DOAJ

【 摘 要 】

Impairedproteindegradationandmitochondrialdysfunction are believed to contribute to neurodegenerativedisorders,includingAlzheimerdisease(AD).In patients suffering from non-hereditary AD, UBB+1, the frameshift variant of ubiquitin B, accumulated in neuronsaffectedbyneurofibrillarytangles,whichis a pathologicalhallmark.Weestablishedayeastmodel expressing high levels of UBB+1, and could demonstrate thatUBB+1 interferedwithboththeubiquitin-proteasome system (UPS) and mitochondrial function. Moreprecisely,UBB+1 promotedthemitochondrion-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-specificUPScomponent,co-existedwithUBB+1 in neurofibrillarytangles.Therefore,ourdatasuggest thataberrantbasicaminoacidsynthesisisacrucial link between UPS dysfunction and mitochondrial damage during AD progression.

【 授权许可】

Unknown