Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
SHR Neuro Krebs Kardio Lipid Stoffw Microb
Braun, RJ; Sommer, C; Leibiger, C; Gentier, RJ; Dumit, VI; Paduch, K; Eisenberg, T; Habernig, L; Trausinger, G; Magnes, C; Pieber, T; Sinner, F; Dengjel, J; Leeuwen, FW; Kroemer, G; Madeo, F.
Modeling non-hereditary mechanisms of Alzheimer disease during apoptosis in yeast.
Microb Cell. 2015; 2(4): 136-138.
Doi: 10.15698/mic2015.04.199
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- Co-Autor*innen der Med Uni Graz
- Pieber Thomas
- Sinner Frank Michael
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- 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.
- Find related publications in this database (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