Disease-specific accumulation of mutant ubiquitin as a marker for proteasomal dysfunction in the brain.
Molecular misreading of the ubiquitin-B (UBB) gene results in a dinucleotide deletion in UBB mRNA. The resulting mutant protein, UBB+1, accumulates in the neuropathological hallmarks of Alzheimer disease. In vitro, UBB+1 inhibits proteasomal proteolysis, although it is also an ubiquitin fusion degradation substrate for the proteasome. Using the ligase chain reaction to detect dinucleotide deletions, we report here that UBB+1 transcripts are present in each neurodegenerative disease studied (tauo- and synucleinopathies) and even in control brain samples. In contrast to UBB+1 transcripts, UBB+1 protein accumulation in the ubiquitin-containing neuropathological hallmarks is restricted to the tauopathies such as Pick disease, frontotemporal dementia, progressive supranuclear palsy, and argyrophilic grain disease. Remarkably, UBB+1 protein is not detected in the major forms of synucleinopathies (Lewy body disease and multiple system atrophy). The neurologically intact brain can cope with UBB+1 as lentivirally delivered UBB+1 protein is rapidly degraded in rat hippocampus, whereas the K29,48R mutant of UBB+1, which is not ubiquitinated, is abundantly expressed. The finding that UBB+1 protein only accumulates in tauopathies thus implies that the ubiquitin-proteasome system is impaired specifically in this group of neurodegenerative diseases and not in synucleinopathies and that the presence of UBB+1 protein reports proteasomal dysfunction in the brain.
Fischer
David F
DF
Graduate School for Neurosciences Amsterdam and Netherlands Institute for Brain Research, Amsterdam, The Netherlands.
De Vos
Rob A I
RA
Van Dijk
Renske
R
De Vrij
Femke M S
FM
Proper
Evelien A
EA
Sonnemans
Marc A F
MA
Verhage
Marian C
MC
Sluijs
Jacqueline A
JA
Hobo
Barbara
B
Zouambia
Mohamed
M
Steur
Ernst N H Jansen
EN
Kamphorst
Wouter
W
Hol
Elly M
EM
Van Leeuwen
Fred W
FW
D000918:Antibody Specificity; D015415:Biomarkers / Q000032:analysis; D001921:Brain / Q000201:enzymology* / Q000378:metabolism; D003546:Cysteine Endopeptidases / Q000378:metabolism*; D006624:Hippocampus / Q000201:enzymology; D006801:Humans; D020961:Lewy Body Disease / Q000378:metabolism / Q000473:pathology; D009097:Multienzyme Complexes / Q000378:metabolism*; D019578:Multiple System Atrophy / Q000378:metabolism / Q000473:pathology; D009154:Mutation; D019636:Neurodegenerative Diseases / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D009474:Neurons / Q000473:pathology; D046988:Proteasome Endopeptidase Complex; D012333:RNA, Messenger / Q000235:genetics; D017384:Sequence Deletion; D024801:Tauopathies / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D025801:Ubiquitin / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D014452:Ubiquitins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*
D015415:Biomarkers; D009097:Multienzyme Complexes; D012333:RNA, Messenger; C479419:UBB protein, human; D025801:Ubiquitin; D014452:Ubiquitins; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex