AI Article Synopsis
- - Drugs that boost 26S proteasome activity could help treat neurodegenerative diseases, as shown by screening over 2,750 compounds to identify effective treatments.
- - The p38 MAPK inhibitor PD169316 emerged as a strong candidate for increasing proteasome activity, and blocking the p38 MAPK pathway further enhances this effect.
- - Activating the 26S proteasome reduces harmful levels of α-synuclein protein, which is linked to cell toxicity, indicating multiple avenues for therapeutic intervention.
Article Abstract
Drugs that increase 26S proteasome activity have potential therapeutic applications in the treatment of neurodegenerative diseases. A chemical genetics screen of over 2,750 compounds using a proteasome activity probe as a readout in a high-throughput live-cell fluorescence-activated cell sorting-based assay revealed more than ten compounds that increase proteasome activity, with the p38 MAPK inhibitor PD169316 being one of the most potent ones. Genetic and chemical inhibition of either p38 MAPK, its upstream regulators, ASK1 and MKK6, and downstream target, MK2, enhance proteasome activity. Chemical activation of the 26S proteasome increases PROTAC-mediated and ubiquitin-dependent protein degradation and decreases the levels of both overexpressed and endogenous α-synuclein, without affecting the overall protein turnover. In addition, survival of cells overexpressing toxic α-synuclein assemblies is increased in the presence of p38 MAPK inhibitors. These findings highlight the potential of activation of 26S proteasome activity and that this can be achieved through multiple mechanisms by distinct molecules.
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| http://dx.doi.org/10.1016/j.chembiol.2017.05.010 | DOI Listing |
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