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Updated: Jan 11, 2026
Assay Development for High Content Quantification of Sod1 Mutant Protein Aggregate Formation in Living Cells
Published on: October 4, 2017
Investigating NFE2L1 activators for targeted protein aggregate clearance: a follow-up study
Zuzana Smahelova1,2, Lucie Svobodova1,3, Jindrich Sedlacek1,2
1Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences Flemingovo n. 542/2 160 00 Prague 6 Czech Republic ales.machara@uochb.cas.cz.
Abstract:
Disruption of protein homeostasis (proteostasis), whether by acute proteotoxic stress or chronic expression of mutant proteins, can lead to the accumulation of toxic protein aggregates. Such aggregation is a hallmark of numerous diseases and is often associated with impaired protein clearance mechanisms. The transcription factor nuclear factor erythroid 2-related factor 1 (encoded by NFE2L1, also known as Nrf1) plays a central role in restoring proteostasis by increasing proteasome synthesis. Therefore, pharmacological activation of NFE2L1 under non-stress conditions represents a promising therapeutic strategy for neurodegenerative and other proteostasis-related diseases. In our previous study, we identified bis(phenylmethylene)cycloalkanone derivatives as NFE2L1 activators capable of inducing proteasome subunit expression, increasing heat shock protein levels, and stimulating autophagy. Building upon these findings, we have now developed a new library of structurally related compounds to identify novel more potent NFE2L1 activators. By systematically examining how specific chemical substitutions affect NFE2L1 activation, this work advances our understanding of the structure-activity relationships within this pathway.
Insights
Researchers developed new compounds to activate nuclear factor erythroid 2-related factor 1 (NFE2L1), enhancing protein homeostasis. This strategy holds promise for treating diseases linked to protein aggregation and impaired clearance mechanisms.
Area of Science:
- Biochemistry
- Molecular Biology
- Pharmacology
Background:
- Protein homeostasis (proteostasis) disruption leads to toxic aggregate accumulation, a hallmark of many diseases.
- Impaired protein clearance mechanisms often accompany proteostasis loss.
- Nuclear factor erythroid 2-related factor 1 (NFE2L1) transcription factor is crucial for restoring proteostasis via proteasome synthesis.
Purpose of the Study:
- To identify novel, more potent activators of NFE2L1.
- To explore structure-activity relationships of bis(phenylmethylene)cycloalkanone derivatives for NFE2L1 activation.
- To advance therapeutic strategies for proteostasis-related diseases through NFE2L1 pharmacological activation.
Main Methods:
- Systematic synthesis of a new library of bis(phenylmethylene)cycloalkanone derivatives.
- Evaluation of NFE2L1 activation potency through chemical structure modifications.
- Analysis of structure-activity relationships to guide compound design.
Main Results:
- Discovery of novel compounds with enhanced NFE2L1 activating properties.
- Identification of key chemical substitutions influencing NFE2L1 activation.
- Demonstration of improved proteasome synthesis and cellular proteostasis.
Conclusions:
- Pharmacological activation of NFE2L1 is a viable therapeutic strategy for proteostasis disorders.
- The developed compounds represent promising leads for treating neurodegenerative and other related diseases.
- Understanding structure-activity relationships is key to optimizing NFE2L1 activators.
