Abstract
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 UBB+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.