The Medical Research Council (MRC) Protein Phosphorylation and Ubiquitylation Unit (PPU) is a major research centre focusing on understanding how signals are transmitted within the body’s cells. Deciphering how disruption of these processes can cause many diseases, such as neurodegeneration, cancer, hypertension and immune disorders, aims to lead to the development of new treatments.
The MRC PPU is based at the University of Dundee School of Life Sciences. Funding will support more than 200 scientific and support staff, and students at the unit to continue their research.
Research by the unit has already contributed to breakthroughs, such as a drug for the cancer melanoma which is now widely used to treat patients. A promising new drug for Parkinson’s disease based on their research is currently in clinical trials.
Other diseases they are studying include motor neuron disease, cancers, intellectual disability, autoimmune bowel diseases such as Crohn’s disease and coeliac disease, and rare diseases such as mitochondrial diseases.
Striving for more health breakthroughs
Science Minister Lord Vallance said:
The work at Dundee University, which we are announcing support for today, is proof of how deep expertise, quality links with industry, and the power of genuine curiosity can deliver meaningful improvements to ordinary people’s lives.
This funding puts the unit on track to strive for still more health breakthroughs, that could help more patients live longer and healthier lives.
Accelerating drug discovery
Professor Dario Alessi, Director of the MRC PPU said:
We are incredibly grateful for the long-term support that our Unit has received from the MRC over the last 34 years. This has enabled our researchers to tackle the most important questions and greatly contributed to our understanding of how derailment of biological pathways causes human diseases including neurodegeneration, diabetes, cancer, and immune dysfunction.
Our mission for the next 5 years will be to work with leading research centres, clinicians, and pharmaceutical companies to translate our discoveries into clinical progress and accelerate drug discovery.
Whilst doing this research we aim to provide our staff with a unique training opportunity working in a collaborative multidisciplinary environment paying attention to improving culture and development best practices.
Culture of collaboration
Professor Patrick Chinnery, Executive Chair of the MRC, said:
The MRC are proud to be investing for a further 5 years in the exceptional research of the MRC PPU in Dundee. They are leaders in conducting rigorous fundamental research and then working with industry to translate those breakthroughs for patient benefit.
The MRC PPU have an outstanding culture of collaboration and sharing their leading research expertise, products and techniques with the wider scientific community.
How new MRC funding is supporting research
Decades of outstanding research lead to ongoing trial of new Parkinson’s drug
A new drug which hopes to treat Parkinson’s disease is currently in clinical trials thanks to many years of painstaking research at the MRC PPU into a signalling protein called leucine rich repeat kinase 2 (LRRK2).
The team of Parkinson’s researchers, led by Professor Alessi, focused on the role of LRRK2 because it is the most frequent cause of inherited Parkinson’s disease.
Parkinson’s disease is a progressive neurodegenerative disorder affecting more than 10 million people worldwide and currently no cure is available. Now, based on their research, a clinical trial, called the ‘LUMA trial’, is testing if a drug that inhibits LRRK2, developed by the companies Denali Therapeutics and Biogen, can slow the progression of Parkinson’s disease.
Dr Esther Sammler, Consultant Neurologist in charge of the LUMA trial in Dundee and newly funded MRC investigator at the MRC PPU, said:
This is a significant step forward in the quest to develop new Parkinson’s treatments and welcoming the first UK patient into this drug trial is testament to the years of hard work undertaken here in Dundee.
Esther leads a team in the MRC PPU to identify biomarkers for LRRK2 and lysosomal dysfunction in Parkinson’s disease and has a joint appointment with the University of Dundee School of Medicine.
Dr Sammler added:
There is still a lot of work ahead of us to establish whether LRRK2 therapeutics will benefit patients. The need to develop new treatments for Parkinson’s remains urgent.
Research into debilitating conditions like inflammatory bowel diseases
Dr Mahima Swamy is newly funded by MRC as a group leader as part of the funding announced today. She leads a team studying potential treatment targets for immune-mediated bowel diseases, including debilitating gut conditions such as Crohn’s disease and the gluten-induced autoimmune coeliac disease.
These are serious illnesses where the body’s own immune system mistakenly attacks the tissues of the gut, which can cause it to become inflamed and ulcerated, resulting in gastrointestinal symptoms. Severe cases of Crohn’s can result in people needing surgery to have the affected part of their gut removed.
Dr Swamy’s research is investigating how the immune system functions in the gut and how cell signalling going awry can cause it to start attacking the body.
Dr Swamy said:
The funding from the MRC will help us to delve deep into the molecular bases of gut diseases. We are excited to get new insights and potential new therapeutic targets for both Crohn’s and coeliac, both chronic autoimmune diseases, that can cause long-term damage.
The ‘world’s longest running collaboration between academic labs and industry’
The MRC PPU leads a unique collaboration, called the Division of Signal Transduction Therapy (DSTT), with leading pharmaceutical companies. It currently works with Boehringer Ingelheim.
Established in 1998, this long-standing collaboration has attracted almost £60 million of investment. It has led to the development and clinical approval of over 40 drugs that target kinases, mainly for the treatment of cancers, with sales of many billions of pounds a year. For example, DSTT researchers played a significant role in aiding GlaxoSmithKline develop an anti-cancer drug, Dabrafenib (Tafinlar), targeting melanoma.
The collaboration aims to develop improved treatments for many diseases, including cancer, arthritis, lupus, hypertension and Parkinson’s disease by accelerating the early-stage development of future drugs.
The pharmaceutical companies provide funding for research and benefit from close interaction with the scientific groups and other partner companies, and the advice, opinions and foresight of leading scientists.
Dr Paul Davies, Deputy Head of the MRC PPU, said:
We believe this is the world’s longest running collaboration between academic labs and industry and it has delivered many new therapies for patients. By working with industry partners we can translate government funded research from the lab to the clinic in a faster and more effective way.
The consortium was recognised by the Department of Trade and Industry as a model of best practice in technology transfer and has directly injected well over £23 million directly into the local economy.
What is protein phosphorylation and ubiquitylation?
Cells inside the body need to be able to send signals to switch processes on and off. Proteins are the work horses inside cells and one of the most common ways that their functions are switched on and off are by attaching and removing chemical tags.
Phosphorylation is the term for when a tiny molecule, called phosphate, is attached to surface of a protein. This can alter the structure of the protein, resulting in changes in its function, such as it being switched on or off. The enzyme that makes the attachment happen is called a kinase, and therefore many drugs target these enzymes.
Ubiquitylation is a similar process for altering protein function, but in this case a tiny protein called ubiquitin is attached to the larger protein.
These processes are so universal that almost all aspects of biology are regulated by reversible protein phosphorylation and ubiquitylation.
Therefore, abnormalities in these pathways are implicated in a vast array of diseases, including cancer, neurodegeneration and inflammation. However, there are thousands of different types of these proteins, so the systems are very complex and many are currently not well understood.
Deciphering how disruptions in phosphorylation and ubiquitylation signals lead to disease will reveal new drug targets and improved strategies to treat many diseases.
Top image: MRC PPU Alessi Lab, Dr Francesca Tonelli performing immunoprecipitation. Credit: Pawel Lis