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

被引：4

作者：

Braun, Ralf J. ^{[1
]}

Sommer, Cornelia ^{[2
,3
]}

Leibiger, Christine ^{[1
]}

Gentier, Romina J. G. ^{[4
]}

Dumit, Veronica I. ^{[5
]}

Paduch, Katrin ^{[1
]}

Eisenberg, Tobias ^{[2
]}

Habernig, Lukas ^{[2
]}

Trausinger, Gert ^{[6
]}

Magnes, Christoph ^{[6
]}

Pieber, Thomas ^{[6
,7
]}

Sinner, Frank ^{[6
,7
]}

Dengjel, Joern ^{[5
]}

van Leeuwen, Fred W. ^{[4
]}

Kroemer, Guido ^{[8
,9
,10
,11
]}

Madeo, Frank ^{[2
,3
]}

机构：

[1] Univ Bayreuth, Inst Cell Biol, D-95440 Bayreuth, Germany

[2] Karl Franzens Univ Graz, NAWI Graz, Inst Mol Biosci, A-8010 Graz, Austria

[3] BioTechMed Graz, A-8010 Graz, Austria

[4] Maastricht Univ, Fac Hlth Med & Life Sci, Dept Neurosci, NI-6229 ER Maastricht, Netherlands

[5] Univ Freiburg, FRIAS Freiburg Inst Adv Studies, BIOSS Ctr Biol Signalling Studies, Dept Dermatol, D-79104 Freiburg, Germany

[6] Joanneum Res, Hlth Inst Biomed & Hlth Sci, A-8010 Graz, Austria

[7] Med Univ Graz, Div Endocrinol & Metab, A-8036 Graz, Austria

[8] INSERM Cordeliers Res Canc, Apoptosis Canc & Immun Lab, Equipe Labellisee Ligue Canc, F-75006 Paris, France

[9] Gustave Roussy Comprehens Canc Ctr, Cell Biol Metabol Platforms, F-94805 Villejuif, France

[10] Hopital Europeen Georges Pompidou, AP HP, Pole Biol, F-75015 Paris, France

[11] Univ Paris 05, Sorbonne Paris Cite, F-75005 Paris, France

来源：

MICROBIAL CELL | 2015年 / 2卷 / 04期

基金：

欧洲研究理事会;

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;

D O I：

10.15698/mic2015.04.199

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 [细胞生物学]; 090102 [作物遗传育种];

摘要：

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 ubiquitinproteasome system (UPS) and mitochondrial function. More precisely, UBB+1 promoted the mitochondrionlocalized 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.

引用

页码：136 / 138

页数：3