Mutant ubiquitin expressed in Alzheimer's disease causes neuronal death.
Ubiquitin-B+1 (UBB+1) is a mutant ubiquitin that accumulates in the neurones of patients with Alzheimer's disease (AD). Here we report on the biochemical and functional differences between ubiquitin and UBB+1 and the effect of the mutant protein on neuronal cells. UBB+1 lacks the capacity to ubiquitinate, and although it is ubiquitinated itself, UBB+1 is not degraded by the ubiquitin-proteasomal system and is quite stable in neuronal cells. Overexpression of UBB+1 in neuroblastoma cells significantly induces nuclear fragmentation and cell death. Our results demonstrate that accumulation of UBB+1 in neurones is detrimental and may contribute to neuronal dysfunction in AD patients.
De Vrij
F M
FM
Graduate School for Neurosciences Amsterdam, Netherlands Institute for Brain Research, Research Group Molecular Misreading, Amsterdam, The Netherlands.
Sluijs
J A
JA
Gregori
L
L
Fischer
D F
DF
Hermens
W T
WT
Goldgaber
D
D
Verhaagen
J
J
Van Leeuwen
F W
FW
Hol
E M
EM
D000255:Adenosine Triphosphate / Q000494:pharmacology; D000256:Adenoviridae / Q000235:genetics; D000544:Alzheimer Disease / Q000235:genetics / Q000473:pathology*; D017209:Apoptosis / Q000502:physiology*; D015153:Blotting, Western; D002467:Cell Nucleus / Q000378:metabolism; D003546:Cysteine Endopeptidases / Q000187:drug effects / Q000378:metabolism; D005822:Genetic Vectors / Q000235:genetics; D006801:Humans; D007763:Lac Operon / Q000235:genetics; D009097:Multienzyme Complexes / Q000187:drug effects / Q000378:metabolism; D009154:Mutation; D009474:Neurons / Q000166:cytology* / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex; D011506:Proteins / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D014407:Tumor Cells, Cultured; D025801:Ubiquitin / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism
D009097:Multienzyme Complexes; D011506:Proteins; D011993:Recombinant Fusion Proteins; D025801:Ubiquitin; D000255:Adenosine Triphosphate; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex