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

Ralf J Braun; Cornelia Sommer; Christine Leibiger; Romina J Gentier; Verónica I Dumit; Katrin Paduch; Tobias Eisenberg; Lukas Habernig; Gert Trausinger; Christoph Magnes; Thomas Pieber; Frank Sinner; Jörn Dengjel; Fred W V Leeuwen; Guido Kroemer; Frank Madeo

doi:10.15698/mic2015.04.199

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

Microb Cell. 2015 Mar 20;2(4):136-138. doi: 10.15698/mic2015.04.199.

Authors

Ralf J Braun¹, Cornelia Sommer², Christine Leibiger¹, Romina J Gentier³, Verónica I Dumit⁴, Katrin Paduch¹, Tobias Eisenberg⁵, Lukas Habernig⁵, Gert Trausinger⁶, Christoph Magnes⁶, Thomas Pieber⁷, Frank Sinner⁷, Jörn Dengjel⁴, Fred W V Leeuwen³, Guido Kroemer⁸, Frank Madeo²

Affiliations

¹ Institute of Cell Biology, University of Bayreuth, 95440 Bayreuth, Germany.
² Institute of Molecular Biosciences, NAWI Graz, University of Graz, 8010 Graz, Austria. ; BioTechMed-Graz, 8010 Graz, Austria.
³ Department of Neuroscience, Faculty of Health, Medicine and Life Sciences, Maastricht University, 6229 ER Maastricht, The Netherlands.
⁴ 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.
⁵ Institute of Molecular Biosciences, NAWI Graz, University of Graz, 8010 Graz, Austria.
⁶ HEALTH Institute for Biomedicine and Health Sciences, Joanneum Research, 8010 Graz, Austria.
⁷ HEALTH Institute for Biomedicine and Health Sciences, Joanneum Research, 8010 Graz, Austria. ; 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. ; 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.

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.

Keywords: aging; apoptosis; autophagy; cell death; microbes; microbial research; microbiome; neurodegeneration; unicellular organism.

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Comment

Grants and funding

We are grateful to the Deutsche Forschungsgemeinschaft (DFG) for grant BR 3706/3-1 to R.J.B., to the Federation of European Biochemistry Societies (FEBS) for short-term fellowship to R.J.B., to the Fonds zur Förderung der wissenschaftlichen Forschung (FWF) for grant DKplus Metabolic and Cardiovascular Disease to C.S., L.H. and F.M., for grants LIPOTOX, I1000, P23490-B12, and P24381-B20 to F.M., and to the Internationale Stichting Alzheimer Onderzoek (ISAO) for project 09-514 to F.W.v.L. T.E. is recipient of an APART fellowship of the Austrian Academy of Sciences at the Institute of Molecular Biosciences, University of Graz. V.I.D. and J.D. are supported by the Excellence Initiative of the German Federal and State Governments through FRIAS and the excellence cluster BIOSS. G.T., C.M., F.S., and T.P. are grateful to the Austrian Federal Ministry for Transport, Innovation and Technology (bmvit) for project Met2Net. G.K. is financed by the Ligue contre le Cancer (équipe labelisée); Agence National de la Recherche (ANR); Association pour la recherche sur le cancer (ARC); Cancéropôle Ile-de-France; Institut National du Cancer (INCa); Fondation Bettencourt-Schueller; Fondation de France; Fondation pour la Recherche Médicale (FRM); the European Commission (ArtForce); the European Research Council (ERC); the LabEx Immuno-Oncology; the SIRIC Stratified Oncology Cell DNA Repair and Tumor Immune Elimination (SOCRATE); the SIRIC Cancer Research and Personalized Medicine (CARPEM); and the Paris Alliance of Cancer Research Institutes (PACRI).