Modulating the ubiquitin-proteasome system in human diseases

The removal of misfolded or otherwise damaged proteins from the intracellular environment is of critical importance for cells as these aberrant proteins can give rise to toxic protein aggregates.

The main proteolytic mechanism for the destruction of misfolded proteins is the ubiquitin-proteasome system (UPS), which is a central player in cellular protein quality control.

The UPS is a complex machinery involving hundreds of different proteins, many of which have distinct enzymatic activities and are, therefore, potentially druggable targets.

In recent years, both inhibition and stimulation of the UPS have gained credit as means for therapeutic intervention in human diseases.

Malignant cells typically produce high levels of misfolded proteins, which render them exquisitely sensitive to drugs that inhibit UPS activity.

On the other hand, stimulation of the UPS may prevent the accumulation of aggregation-prone proteins in neurons, which plays a central role in a variety of age-related, neurodegenerative disorders, such as Alzheimer’s disease.

We have previously established tools for the monitoring of UPS activity in normal and malignant cells and started a drug discovery campaign for UPS inhibitors.

Here we propose 1) to study the mode of action of a novel inhibitor of the UPS with anti-tumor properties, 2) explore the potential of two cellular targets for stimulating the UPS and 3) inveistigate the status of the UPS in human embryonic stem cell-derived neuronal lineages.