Accumulation of Basic Amino Acids at Mitochondria Dictates the Cytotoxicity of Aberrant Ubiquitin

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-...

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Vydané v:Cell reports (Cambridge) Ročník 10; číslo 9; s. 1557 - 1571
Hlavní autori: Braun, Ralf J., Sommer, Cornelia, Leibiger, Christine, Gentier, Romina J.G., Dumit, Verónica I., Paduch, Katrin, Eisenberg, Tobias, Habernig, Lukas, Trausinger, Gert, Magnes, Christoph, Pieber, Thomas, Sinner, Frank, Dengjel, Jörn, van Leeuwen, Fred W., Kroemer, Guido, Madeo, Frank
Médium: Journal Article
Jazyk:English
Vydavateľské údaje: United States Elsevier Inc 10.03.2015
Cell Press
Elsevier
ISSN:2211-1247, 2211-1247
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Shrnutí: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. [Display omitted] •UBB+1 co-exists with the UPS component VMS1 in neurofibrillary tangles•UBB+1 accumulation impairs the UPS and mitochondria, triggering cell death•UBB+1 causes accumulation of basic amino acids at mitochondria•Vms1 reverts UBB+1-triggered basic amino acid accumulation and cell death Braun et al. demonstrate that basic amino acid accumulation at mitochondria is a decisive toxic event upon cellular accumulation of UBB+1, an Alzheimer’s-disease-associated ubiquitin variant. Triggering the mitochondrion-specific branch of the ubiquitin-proteasome system is sufficient to prevent UBB+1-triggered cytotoxicity, which has potentially far-reaching pathophysiological implications.
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ISSN:2211-1247
2211-1247
DOI:10.1016/j.celrep.2015.02.009