Could a new drug-development strategy help protect brain cells from damage caused by neurodegenerative diseases? Researchers at the University of California, Berkeley, have identified a promising approach that activates specialised enzymes to eliminate multiple harmful proteins and improve cellular health.
The study, published in Science, describes a method that could help protect neurons by improving mitochondrial function. So far, researchers have demonstrated its potential in laboratory experiments using engineered cells and human stem cell-derived neurons.
Targeting Harmful Proteins to Protect Cells
Mitochondria play an essential role in producing the energy that cells need to function. However, the accumulation of misfolded or dysfunctional proteins can interfere with mitochondrial activity, potentially contributing to nerve and muscle degeneration.
One approach to tackling this problem is targeted protein degradation (TPD), which removes harmful proteins rather than simply blocking their activity. Although this strategy has shown promise in areas such as cancer and inflammatory diseases, it generally focuses on individual proteins. This limits its potential against complex diseases involving multiple dysfunctional proteins.
New Strategy Activates Protein-Clearing Enzymes
To overcome this limitation, researchers explored an enzyme called E3 ligase CUL2FEM1B, which helps remove harmful proteins that obstruct the channels responsible for transporting proteins into mitochondria.
However, BEX proteins naturally inhibit this enzyme and restrict its activity. The researchers therefore investigated whether small molecules could displace these inhibitory proteins and restore the enzyme’s ability to clear harmful proteins.
After screening approximately 120,000 compounds, the team identified two promising molecules: BEX displacer 1 (BD1) and BEX displacer 2 (BD2).
Further experiments showed that BD2 could displace BEX proteins, allowing the E3 enzyme to break down several natural target proteins. This improved protein transport into mitochondria and increased mitochondrial respiration.
The researchers named this approach stimulated protein degradation (SPD). Unlike conventional targeted protein degradation, SPD activates an existing cellular protein-clearing mechanism to eliminate multiple harmful proteins.
Potential Benefits for Neurodegenerative Diseases
The researchers next tested BD2 in cellular models of two conditions: COX deficiency syndrome, a rare genetic metabolic disorder, and Friedreich’s ataxia, an inherited neurodegenerative disease that affects the nervous system, muscle coordination and balance.
In experiments involving COX deficiency syndrome, BD2 restored mitochondrial respiratory function and protected laboratory-grown neurons against premature cell death.
Similarly, the compound protected neurons in models of Friedreich’s ataxia. Its protective effect on cell survival was comparable to that of omaveloxolone, an approved treatment for the condition, in these laboratory experiments.
Importantly, the researchers also found that BD2 restored cellular function without causing detectable oxidative stress or mitochondrial damage under the conditions tested.
Further Research Needed Before Clinical Use
Despite these encouraging findings, the new approach remains at an early research stage. Researchers must conduct further studies to determine whether these compounds can safely reach affected tissues, particularly the brain.
Additional research will also help establish whether similar inhibitor-displacement strategies can activate other protective E3 ligases and offer new treatment possibilities for diseases associated with cellular stress.
The researchers believe BD2 could provide a starting point for developing treatments for several conditions linked to impaired mitochondrial function. However, its safety and effectiveness in animals and humans remain to be established.
As reported by Medical Xpress, the findings highlight the potential of stimulated protein degradation as a new drug-development strategy that could help protect neurons and address multiple disease-causing proteins simultaneously.