Modeling non-hereditary mechanisms of Alzheimer disease during apoptosis in yeast
Authors:Ralf J. Braun1,#, Cornelia Sommer2,3,#, Christine Leibiger1,#, Romina J.G. Gentier4,#, Verónica I. Dumit5, Katrin Paduch1, Tobias Eisenberg2, Lukas Habernig2, Gert Trausinger6, Christoph Magnes6, Thomas Pieber6,7, Frank Sinner6,7, Jörn Dengjel5, Fred W. van Leeuwen4, Guido Kroemer8-11, and Frank Madeo2,3
doi: 10.15698/mic2015.04.199
Volume 2, pp. 136 to 138, published 20/03/2015.
1 Institute of Cell Biology, University of Bayreuth, 95440 Bayreuth, Germany.
2 Institute of Molecular Biosciences, NAWI Graz, University of Graz, 8010 Graz, Austria.
3 BioTechMed-Graz, 8010 Graz, Austria.
4 Department of Neuroscience, Faculty of Health, Medicine and Life Sciences, Maastricht University, 6229 ER Maastricht, The Netherlands.
5 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.
6 HEALTH Institute for Biomedicine and Health Sciences, Joanneum Research, 8010 Graz, Austria.
7 Division of Endocrinology and Metabolism, Medical University of Graz, 8036 Graz, Austria.
8 Apoptosis, Cancer & Immunity Laboratory, Team 11, Equipe labellisée Ligue contre le Cancer, INSERM Cordeliers Research Cancer, 75006 Paris, France.
9 Cell Biology & Metabolomics Platforms, Gustave Roussy Comprehensive Cancer Center, 94805 Villejuif, France.
10 Pôle de Biologie, Hôpital Européen Georges Pompidou, AP-HP, 75015 Paris, France.
11 Université Paris Descartes, Sorbonne Paris Cité, 75005 Paris, France.
Keywords:
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
Corresponding Author(s):
Conflict of interest statement:
The authors declare no conflict of interest.
Please cite this article as:
Ralf J. Braun, Cornelia Sommer, Christine Leibiger, Romina J.G. Gentier, Verónica I. Dumit, Katrin Paduch, Tobias Eisenberg, Lukas Habernig, Gert Trausinger, Christoph Magnes, Thomas Pieber, Frank Sinner, Jörn Dengjel, Fred W. van Leeuwen, Guido Kroemer, and Frank Madeo (2015). Modeling non-hereditary mechanisms of Alzheimer disease during apoptosis in yeast. Microbial Cell 2(4): 136-138.
© 2015 Braun et al. This is an open-access article released under the terms of the Creative Commons Attribution (CC BY) license, which allows the unrestricted use, distribution, and reproduction in any medium, provided the original author and source are acknowledged.
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+1 interfered with both the ubiquitin-proteasome system (UPS) and mitochondrial function. More precisely, UBB+1 promoted 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+1 in 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.