The ubiquitin/proteasome system in neurodegenerative diseases and cancer – Nico Dantuma's Group

Our major objectives are to understand the role of the ubiquitin/proteasome system in the development of neurodegenerative diseases and cancer and to explore the therapeutic potential of modifiers of this system.

People standing next to each other by a railing.
Microscopic picture of a neuronal cell

Our research

Regulated degradation of proteins in our cells is executed by the ubiquitin/proteasome system. As such the ubiquitin/proteasome system is critical for the degradation of key regulators that are implicated in signaling, regulation of the cell cycle and induction of apoptosis. Moreover, the ubiquitin/proteasome system is also important for protein quality control given its role in the destruction of abnormal, misfolded and dysfunctional proteins. Hundreds of enzymes are involved in the coordinated efforts of the ubiquitin/proteasome system in protein degradation underscoring its potential as therapeutic target for a broad variety of diseases. Tumor cells are in particularly sensitive to inhibition of the ubiquitin/proteasome system and the first proteasome inhibitor has recently been introduced in the clinic for the treatment of multiple myeloma, a type of blood cancer. Interestingly, enhancing proteasomal degradation of proteins linked to neurodegenerative diseases can reduce their toxicity.

We have developed tools to study the ubiquitin/proteasome system in cellular and animal models. Real-time imaging of fluorescently tagged proteins in living cells plays an important role in our research. These experimental approaches are used to gain insights in the functional status of the ubiquitin/proteasome system in various diseases and to decipher the molecular mechanisms that are responsible for alterations caused by disease-associated proteins. In addition, we use these models in the development of novel compounds that target the ubiquitin/proteasome system. We are also exploring the non-proteolytic role of ubiquitin in the cellular response to DNA damage.

Publications

Selected publications

Funding

Grants

  • Swedish Research Council
    1 January 2025 - 31 December 2027
    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.
  • Swedish Brain Foundation
    1 July 2023 - 30 June 2025
  • Swedish Research Council
    1 January 2022 - 31 December 2024
  • Target identification of a novel inhibitor of the ubiquitin-proteasome system and autophagy
    Novo Nordisk Foundation
    1 April 2020 - 31 March 2021
  • In vivo validation of a novel inhibitor of the ubiquitin/proteasome system
    Novo Nordisk Foundation
    1 August 2019 - 31 July 2020
  • Deutsche Forschungsgemeinschaft
    1 January 2018 - 31 December 2021

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