Abstract
The proteolytic machinery activity diminishes with age, leading to abnormal accumulation of aberrant proteins; furthermore, a decline in protein degradation capacity is associated with multiple age-related proteinopathies. Cellular proteostasis can be maintained via the removal of ubiquitin (Ub)-tagged damaged and redundant proteins by the ubiquitin-proteasome system (UPS). However, during aging, central nervous system (CNS) cells begin to express a frameshift-mutated Ub, UBB+1. Its accumulation is a neuropathological hallmark of tauopathy, including Alzheimer’s disease and polyglutamine diseases. Mechanistically, in cell-free and cell-based systems, an increase in the UBB+1 concentration disrupts proteasome processivity, leading to increased aggregation of toxic proteins. On the other hand, a low level of UBB+1 improves stress resistance and extends lifespan. Here we summarize recent findings regarding the impact of UBB+1 on Ub signaling and neurodegeneration. We also review the molecular basis of how UBB+1 affects UPS components as well as its dose-dependent switch between cytoprotective and cytotoxic roles.
Highlights
Age-related impairment of protein degradation affects protein homeostasis networks, causing enhanced accumulation of damaged proteins that can be cytotoxic and shorten lifespan
Subsequent studies confirmed the involvement of UBB+1 in several other neurodegenerative diseases (i.e., Pick disease and progressive supranuclear palsy) as well as in polyglutamine diseases (i.e., Huntington’s disease and spinocerebellar ataxia type 3)
UBB+1 can elicit pleiotropic effects depending on its expression level
Summary
Age-related impairment of protein degradation affects protein homeostasis (proteostasis) networks, causing enhanced accumulation of damaged proteins that can be cytotoxic and shorten lifespan. Deletion of ARG5,6, ARG8, and LYS1, which are involved in amino acid metabolism, rescued the clonogenic potential of cells expressing UBB+1 in response to acetate-induced oxidative stress. These findings indicate that high UBB+1 levels enhance the biosynthesis of the basic amino acids arginine, ornithine, and lysine, potentially aggravating its cytotoxicity. This effect is only robustly reflected at the protein level for Hsp and Hsp (only a moderate increase in Hsp90a has been found) To examine how these cells manage oxidative stress upon UBB+1 expression, cell survival was measured based on mitochondrial activity after tert-butyl hydroperoxide (tBHP, a strong oxidant) treatment for 24 h. Due to the role of 14-3-3ζ in the regulation of the unfolded protein response in the mouse hippocampus (Brennan et al, 2013), its elevated levels associated with UBB+1 expression might protect these cells from ER stress
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