A new approach to stimulating protein degradation could expand the therapeutic potential of targeted treatments for complex neurodegenerative diseases involving multiple dysfunctional proteins, according to a new study. Targeted protein degradation (TPD) is an emerging therapeutic strategy that eliminates disease-causing proteins rather than simply blocking their activity. By degrading rather than inhibiting proteins, TPD can produce more sustained effects and disable protein functions that have been linked to the development of drug resistance, offering potential advantages in treating cancer, autoimmune disease, and inflammatory syndromes. However, existing TPD approaches target individual proteins, limiting their applicability to treat complex neurodegenerative and mitochondrial diseases, which often involve dysregulation of several proteins. Previous research has identified E3 ligases that respond to cellular stress by identifying and degrading multiple defective proteins that accumulate in degenerative diseases.

Leveraging these observations, Srividya Chandrasekhar and colleagues developed simulated protein degradation (SPD), a strategy that uses small molecule agonists to activate these stress-responsive enzymes, enabling the simultaneous degradation of multiple disease-causing proteins. Using a differential screening approach, Chandrasekhar et al. identified the reductive stress response E3 ligase CUL2^FEM1B, which protects mitochondrial function by removing proteins that obstruct mitochondrial import. In experiments, the authors show that activating the ligase improved mitochondrial protein import and energy production, restoring cellular function and neuronal survival in models of mitochondrial and neurodegenerative disorders, including Friedreich’s ataxia. The approach demonstrated high potency and specificity without causing oxidative stress or mitochondrial damage. Beyond its potential as a standalone therapy, Chandrasekhar et al. note that SPD could also complement existing TPD therapies by improving treatment specificity and enabling the combined removal of both natural protein targets and disease-associated proteins, offering a promising new direction for treating complex diseases. In a related Perspective, Ramanujan Hegde discusses the study and its findings in greater detail.

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