Role of the Ubiquitin C-Terminal Hydrolase L1-Modulated Ubiquitin Proteasome System in Auditory Cortex Senescence

Abstract

Background/Aims: According to recent studies, central auditory impairments are closely related to neurodegenerative diseases. However, the mechanism of central presbycusis remains unclear. Ubiquitin C-terminal hydrolase L1 (UCHL1) is important in maintaining proteasomal activity; however, the detailed mechanism has not yet been fully elucidated. This study aims to investigate the molecular alterations involved in UCHL1 regulation during auditory cortex aging. Methods:<smlcap>D</smlcap>-Galactose (<smlcap>D</smlcap>-gal) induces oxidative stress and senescence in the auditory cortex, as reported in our previous studies. Primary auditory cortex cells were treated with <smlcap>D</smlcap>-gal for 72 h or 5 days. The proteins related to the ubiquitin proteasome system (UPS) and proteasomal activities were evaluated. UCHL1 was overexpressed, and the effects of UCHL1 on the UPS and proteasomal activity were analyzed. Results: Proteasomal activity was elevated at 72 h and decreased at 5 days in <smlcap>D</smlcap>-gal-treated primary auditory cortex cells. We also found that overexpression of UCHL1 increased the UPS-related proteins UBE1, PSMA7, ubiquitinated proteins, and monoubiquitin, and proteasomal activity. Conclusion: The results suggest that UCHL1 may modify the aging process in the auditory cortex by regulating UPS- related proteins.

Galactose-Induced Skin Aging: The Role of Oxidative Stress

“…It has been reported that the ubiquitin-proteasome system (UPS) and autophagy are involved in the removal of AGEs [124]. However, the abovementioned factors themselves can have negative influence on the protein degradation systems in cells [125]. It was established that D-gal can disturb ubiquitin-proteasome system [125] and thus enhance the levels of glycated proteins in the cells.…”

“…However, the abovementioned factors themselves can have negative influence on the protein degradation systems in cells [125]. It was established that D-gal can disturb ubiquitin-proteasome system [125] and thus enhance the levels of glycated proteins in the cells. It should also be noted that autophagic flux alterations were detected recently in D-gal-treated skin fibroblasts [111,117].…”

Redox regulation of proteasome function

“…UV radiation promotes protein oxidation leading to increased cellular oxidative stress levels and decreased levels of proteasome activities without however affecting the 20S or 26S proteasome conformation [94] . D-galactose (D-gal) is a constituent of human diet and has been found to induce oxidative stress and to promote senescence in primary auditory cortex cells by affecting the proteasome activity [95] . Overexpression of the ubiquitin C-Terminal Hydrolase L1 (UCHL1) leads to increased proteasome activity and alters the aging process in the auditory cortex.…”

The ubiquitin-proteasome system in normal hearing and deafness

“…When D-gal is used to induce presbycusis in neurons of the auditory cortex, Uchl1 (a DUB already known to be involved in gentamicin-induced auditory cell death, see Section 5.2) is upregulated, increasing proteasomal activity to provide a compensatory action to the mild oxidative stress. However, the continuous production of ROS decreases Uchl1 and proteasomal activity ( Zhang et al, 2017 ). These results indicate that Uchl1 may play an essential role in maintaining the mono-Ub pool to activate the UPS during auditory cortex aging.…”