Journal
CELL REPORTS
Volume 10, Issue 9, Pages 1557-1571Publisher
CELL PRESS
DOI: 10.1016/j.celrep.2015.02.009
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Funding
- Deutsche Forschungsgemeinschaft (DFG) [3706/3-1]
- Federation of European Biochemistry Societies (FEBS)
- Fonds zur Forderung der wissenschaftlichen Forschung (FWF) for grant DKplus Metabolic and Cardiovascular Disease
- Internationale Stichting Alzheimer Onderzoek (ISAO) [09-514]
- APART fellowship of the Austrian Academy of Sciences at the Institute of Molecular Biosciences
- Excellence Initiative of the German Federal Government through FRIAS and
- excellence cluster BIOSS
- Excellence Initiative of the State Government through FRIAS
- Austrian Federal Ministry for Transport, Innovation and Technology (bmvit) for project Met2Net
- Ligue contre le Cancer (equipe labelisee)
- Agence National de la Recherche (ANR)
- Association pour la recherche sur le cancer (ARC)
- Canceropole Ile-de-France
- Institut National du Cancer (INCa)
- Fondation Bettencourt-Schueller
- Fondation de France
- Fondation pour la Recherche Medicale (FRM)
- European Commission (ArtForce)
- European Research Council (ERC)
- LabEx Immuno-Oncology
- SIRIC Stratified Oncology Cell DNA Repair and Tumor Immune Elimination (SOCRATE)
- SIRIC Cancer Research and Personalized Medicine (CARPEM)
- Paris Alliance of Cancer Research Institutes (PACRI)
- University of Bayreuth
- University of Graz
- [LIPOTOX]
- [I1000]
- [P23490-B12]
- [P24381-B20]
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Neuronal accumulation of UBB+1, a frameshift variant of ubiquitin B, is a hallmark of Alzheimer's disease (AD). How UBB+1 contributes to neuronal dysfunction remains elusive. Here, we show that in brain regions of AD patients with neurofibrillary tangles UBB+1 co-exists with VMS1, the mitochondrion-specific component of the ubiquitin-proteasome system (UPS). Expression of UBB+1 in 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.
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