Patience and passion in the search for improved Parkinson’s treatment
Published on 6 November 2019
Our researchers are finding new ways to approach the complex puzzle that is Parkinson’s disease, offering hope of breakthroughs in diagnosis and treatment
The problems facing researchers tasked with understanding the mechanisms involved in the development of Parkinson’s disease are stark. More than 200 years have passed since the disabling neurodegenerative disease was first identified and still there is no cure and no way of slowing its progress.
Professor Miratul Muqit, a researcher at the University of Dundee’s School of Life Sciences and a consultant neurologist, describes the scale of the difficulty by noting that the only treatments he can offer his patients are the same ones that were being prescribed by doctors before he was born.
This is something he and colleagues Professor Dario Alessi, Director of the MRC Protein Phosphorylation and Ubiquitylation Unit, and Dr Esther Sammler, consultant neurologist and Principal Investigator at the Unit, are doggedly working to change.
Professor Miratul Muqit
He and his colleagues have already made progress. Professor Muqit was part of the team that identified and characterised the first mutations of the PINK1 gene in families with early onset Parkinson’s disease. He has continued to focus his efforts on PINK1 with the goal of developing new therapies for patients.
Recent successes have including finding the PINK1 protein substrates Parkin and Ubiquitin, discovering that Parkin and Ubiquitin form a complex to cope with mitochondrial damage, solving the atomic structure of PINK1 with Prof Daan van Aalten, and confirming the central importance of the PINK1-Parkin switch mechanism in Parkinson’s patients.
Meanwhile Professor Alessi has directed his attention to LRRK2, an important target enzyme that is activated in Parkinson’s. He co-ordinated a major multi-disciplinary international collaboration to identify the physiological endogenous substrates of LRRK2. This resulted in the discovery that LRRK2 directly phosphorylated a subset of the Rab GTPases including Rab8, Rab10 and Rab12.
In 2016 Professor Alessi’s lab developed new methods to assess LRRK2 phosphorylation of endogenous Rab isoforms that enables the activity of endogenous LRRK2 to be monitored. So far more than 14 Rab proteins have been identified as substrates for LRRK2. This work has also allowed Professor Alessi and Dr Sammler to develop assays and reagents for measuring LRRK2 activity and they are now working on developing new therapeutics targeting the enzyme to treat the disease.
For Professor Muqit, who developed his interest in PINK1 while based at the National Hospital for Neurology and Neurosurgery in London, moving north to Dundee was vital to his ambitions of finding solutions to the Parkinson’s treatment problem although he acknowledges his decision was greeted with surprise by some of his colleagues.
“When I told them I was moving to Dundee they thought I was crazy,” he laughs. “Once you are in London it is easy to get comfortable in that environment and stay there. There is a career path where you become a clinical expert, work in the NHS and maybe in private practice. There is the opportunity for research but it is a different kind of research.
“The expertise in the National Hospital in Neurology is mainly clinical. I needed to come to an environment where the expertise is at the molecular level and where there is research into proteins and I am very lucky to have that in Dundee. There are maybe a few places in the US where there are magnificent teaching hospitals side by side with excellent researchers in basic science but it’s not usual.
Professor Miratul Muqit
"The advances we have made could only have been done here, and there are more discoveries to be made. Understanding how PINK1 enzymes function will provide new therapies for Parkinson's patients. Many companies are now developing drugs that can activate parkin and there is also work being done on PINK1.”
A supportive environment and a belief and trust in the work being carried out by research teams have also been key factors in the progress made in the field by Professor Alessi, whose work on protein kinases has won him a host of prestigious scientific awards including the Colworth Medal and the EMBO Gold medal as well as making him one of the world’s most cited biochemists.
He decided to switch the focus of his research from diabetes, cancer and high blood pressure to Parkinson’s disease after the 2004 discovery by Gasser and Singleton that protein kinases, and LRRK2 specifically, were mutated in some cases of the condition.
“Until then no one had considered that protein kinases were implicated in Parkinson’s,” explains Professor Alessi. “We recognised that what was needed was to roll up our sleeves and look at this at the molecular level. We know how to study kinases here. That’s what we do. We had one question which was to find out what proteins LRRK2 targets.”
Finding an answer proved a long, frustrating but ultimately successful journey resulting in the discovery of Rab isoforms.
“It took far longer than we anticipated. A total of 12 years from 2004 to 2016. We wanted to understand how mutations affect LRRK2. We didn’t know what was happening in the cells. We tried everything we had ever tried before and it did not work. It was the hardest problem I had ever worked on. I had colleagues tell me they no longer wanted to work on it. There was always the chance funders would pull out. We had to work very hard to persuade funders to believe in us. It was very, very difficult.
“But if something is hard then you put even more energy into finding a solution. Of course I believed we would succeed. But yes I had doubts. Having doubts is part of the scientific process. You are actively trying to prove your hypothesis wrong.”
Professor Dario Alessi
Professor Alessi added that there was more to his motivation than simply solving a scientific puzzle.
“There are many, many people with Parkinson’s disease. It is the second most common neurodegenerative condition with millions affected worldwide. As the years went by it took on added urgency. We had to keep going but it was very, very painstaking work. We threw the kitchen sink at it. And when we discovered Rabs, we didn’t celebrate. We just moved straight on to the next problem.
“We have a lot of patient contact and it is meeting the patients that keeps us going. They are very inspirational. That is what drives us. It becomes a mission. It certainly isn’t a normal job. We put our heart and soul into it. If you answer one question it raises another ten.”
As a result of that work, clinical trials are now underway to test new inhibitors. The assays and reagents for measuring LRRK2 activity developed by Professor Alessi and Dr Sammler, are also being used by industry, both in drug development and as clinical biomarkers of drug efficacy in the first clinical trials testing the effectiveness of new drugs to treat Parkinson’s patients.
Dr Sammler, who is chair of the Tayside Parkinson’s forum and a member of the Neurogenetics Advisory Group of the Association of British Neurologists, is optimistic that the goal of improved treatment is now closer than ever.
“The LRKK2 kinase offers the prospect for disease-modifying treatments,” she says. “The assay to interrogate this pathway is a major step forward in providing insight into the physiological activity of the pathway in humans. It will allow the identification of individuals with increased levels of LRRK2 controlled Rab10 phosphorylation and potentially aid in pharmacokinetic and target engagement studies in future LRRK2 inhibitor trials.”
Press Office, University of Dundeepress@dundee.ac.uk