Science· 2026Q1
Stimulated protein degradation to promote mitochondrial function and neuronal survival
- 1citations
- Q1SCImago
- 2026year
Short summary
A new strategy called stimulated protein degradation (SPD) uses activators of the CUL2 FEM1B E3 ligase to eliminate multiple pathogenic proteins, thereby improving mitochondrial function and neuronal survival in models of neurodegenerative diseases.
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Key points
- Stimulated protein degradation (SPD) is a new strategy using E3 ligase agonists to eliminate multiple pathogenic proteins.
- Activators of the CUL2 FEM1B E3 ligase boost degradation of physiological substrates.
- SPD improves mitochondrial import and electron transport chain assembly.
- CUL2 FEM1B agonists preserved mitochondrial function and neuronal survival in models of neurodegenerative COX deficiency syndrome and Friedreich’s ataxia.
AI-generated from the title and abstract; the full text is not read.
Abstract
Targeted protein degradation is a promising modality to treat cancer or inflammation, but whether it can provide a similar benefit for disorders caused by pervasive protein dysregulation is unclear. We describe stimulated protein degradation (SPD) as a strategy that leverages agonists of stress-responsive E3 ubiquitin ligases to simultaneously eliminate multiple pathogenic factors. Specifically, we show that activators of the reductive stress response E3 CUL2 FEM1B boost degradation of multiple physiological substrates to improve mitochondrial import and electron transport chain assembly. In this manner, CUL2 FEM1B agonists preserve mitochondrial function and neuronal survival in models of neurodegenerative COX deficiency syndrome and Friedreich’s ataxia. By activating E3 ligases that evolved to safeguard cellular integrity, SPD expands the use of compound-induced protein degradation to complex pathologies of high unmet need.
The authors' abstract, as published at the source. Science, 2026 · DOI ↗
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Field: Molecular Biology
Molecular BiologyBiochemistry, Genetics and Molecular Biology