Abstract
A common pathological hallmark of age-related neurodegenerative diseases is the intracellular accumulation of protein aggregates such as α-synuclein in Parkinson's disease, TDP-43 in ALS, and tau in Alzheimer's disease. Enhancing intracellular clearance of aggregation-prone proteins is a plausible strategy for slowing progression of neurodegenerative diseases and there is great interest in identifying molecular targets that control protein turnover. One of the main routes for protein degradation is through the proteasome, a multisubunit protease that degrades proteins that have been tagged with a polyubiquitin chain by ubiquitin activating and conjugating enzymes. Published data from cellular models indicate that Ubiquitin-specific protease 14 (USP14), a deubiquitinating enzyme (DUB), slows the degradation of tau and TDP-43 by the proteasome and that an inhibitor of USP14 increases the degradation of these substrates. We conducted similar experiments designed to evaluate tau, TDP-43, or α-synuclein levels in cells after overexpressing USP14 or knocking down endogenous expression by siRNA.
Highlights
Research on the ubiquitin-proteasome system has far reaching implications for the development of drugs to treat illnesses associated with the accumulation of misfolded proteins, including Alzheimer’s and Parkinson’s disease (Ciechanover & Kwon, 2015)
A critical role of Ubiquitin-specific protease 14 (USP14) in stabilizing cellular ubiquitin levels was demonstrated in vivo in USP14 deficient axJ mice which display decreased ubiquitin levels in all tissues with the greatest loss observed at synaptic terminals (Anderson et al, 2005; Wilson et al, 2002)
For two proteins involved in neurodegenerative diseases, tau and TDP-43, inhibition of proteasomal degradation by USP14 was dependent on its deubiquitinating activity, since the catalytically inactive mutant had no effect (Lee et al, 2010)
Summary
Research on the ubiquitin-proteasome system has far reaching implications for the development of drugs to treat illnesses associated with the accumulation of misfolded proteins, including Alzheimer’s and Parkinson’s disease (Ciechanover & Kwon, 2015). For two proteins involved in neurodegenerative diseases, tau and TDP-43, inhibition of proteasomal degradation by USP14 was dependent on its deubiquitinating activity, since the catalytically inactive mutant had no effect (Lee et al, 2010). This led to the hypothesis that deubiquitination of substrates by USP14 at a faster rate than the proteasome initiates degradation could cause rejection of otherwise competent substrates from the proteasome. Inhibition of USP14 was proposed as a therapeutic strategy to enhance proteasomal function in neurodegenerative diseases in which these proteins accumulate
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
