Frameshift proteins in Alzheimer's disease and in other conformational disorders: time for the ubiquitin-proteasome system.
Neuronal homeostasis requires a constant balance between biosynthetic and catabolic processes. Eukaryotic cells primarily use two distinct mechanisms for degradation: the proteasome and autophagy of aggregates by the lysosomes. We focused on the ubiquitin-proteasome system (UPS) and discovered a frameshift protein for ubiquitin (UBB+1), that accumulates in the neuritic plaques and tangles in patients with Alzheimer's disease (AD). UBB+1, unable to tag proteins to be degraded, has been shown to be a substrate for ubiquitination and subsequent proteasomal degradation. If UBB+1 is accumulated, it inhibits the proteasome, which may result in neuronal death. We showed that UB+1 is also present in other tauopathies (e.g. Pick's disease) and in several polyglutamine diseases, but remarkably not in synucleinopathies (e.g. Parkinson's disease). Accumulation of UBB+1-being a reporter for proteasomal dysfunctioning- thus differentiates between these conformational diseases. The accumulation of UBB+1 causes a dysfunctional UPS in these multifactorial neurodegenerative diseases. Novel transgenic mouse models and large-scale expression profiling and functional analyses of enzymes of the UPS compounds - enabling us to identify the targets of the UPS in these conformational diseases - may now pave the way for intervention and treatment of AD.
van Leeuwen
F W
FW
Netherlands Institute for Brain Research, Meibergdreef 33, 1105 AZ Amsterdam, The Netherlands. f.van.leeuwen@nih.knaw.nl
Hol
E M
EM
Fischer
D F
DF
D000544:Alzheimer Disease / Q000473:pathology*; D000818:Animals; D001921:Brain / Q000473:pathology*; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D016874:Neurofibrillary Tangles / Q000378:metabolism / Q000473:pathology; D010455:Peptides / Q000172:deficiency; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D011487:Protein Conformation; D025801:Ubiquitin / Q000378:metabolism*; D016875:tau Proteins / Q000378:metabolism
D010455:Peptides; D025801:Ubiquitin; D016875:tau Proteins; C097188:polyglutamine; D046988:Proteasome Endopeptidase Complex