Small-molecule activators of NRF1 transcriptional activity prevent protein aggregation
Jazyk angličtina Země Francie Médium print-electronic
Typ dokumentu časopisecké články
PubMed
39884031
DOI
10.1016/j.biopha.2025.117864
PII: S0753-3322(25)00058-7
Knihovny.cz E-zdroje
- Klíčová slova
- DDI2, NGLY1, NRF1(NFE2L1), Proteasome, Protein aggregates, Small molecules,
- MeSH
- aktivace transkripce účinky léků MeSH
- autofagie účinky léků MeSH
- Caenorhabditis elegans * účinky léků metabolismus MeSH
- faktor 1 související s NF-E2 metabolismus genetika MeSH
- knihovny malých molekul farmakologie MeSH
- lidé MeSH
- patologická konformace proteinů metabolismus farmakoterapie MeSH
- proteasomový endopeptidasový komplex * metabolismus MeSH
- proteinové agregáty * účinky léků MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- faktor 1 související s NF-E2 MeSH
- knihovny malých molekul MeSH
- proteasomový endopeptidasový komplex * MeSH
- proteinové agregáty * MeSH
Intracellular protein aggregation causes proteotoxic stress, underlying highly debilitating neurodegenerative disorders in parallel with decreased proteasome activity. Nevertheless, under such stress conditions, the expression of proteasome subunits is upregulated by Nuclear Factor Erythroid 2-related factor 1 (NRF1), a transcription factor that is encoded by NFE2L1. Activating the NRF1 pathway could accordingly delay the onset of neurodegenerative and other disorders with impaired cell proteostasis. Here, we present a series of small-molecule compounds based on bis(phenylmethylen)cycloalkanones and their heterocyclic analogues, identified via targeted library screening, that can induce NRF1-dependent downstream events, such as proteasome synthesis, heat shock response, and autophagy, in both model cell lines and Caenorhabditis elegans strains. These compounds increase proteasome activity and decrease the size and number of protein aggregates without causing any cellular stress or inhibiting the ubiquitin-proteasome system (UPS). Therefore, our compounds represent a new promising therapeutic approach for various protein conformational diseases, including the most debilitating neurodegenerative diseases.
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