Understanding Signalling Pathways Mutated in Inherited Disorders

Lead Research Organisation: University of Dundee

Abstract

My laboratory focuses on unravelling the roles played by an important class of enzymes that are implicated in human disease, that control a biological process known as “protein phosphorylation”. Many diseases including Parkinson’s disease, cancer and high blood pressure, are caused by alterations in specific pathways that regulate protein phosphorylation. My research programme will be based on deciphering the molecular details of protein phosphorylation pathways that are associated with Parkinson’s Disease (LRRK2), cancer (SGK3 pathway) and hypertension (WNK pathway). The overarching goal of our research is to discover how disruptions in enzymes that regulate phosphorylation are linked to human disease. We aim to harness this information and work with clinicians as well as pharmaceutical companies to develop improved strategies to better treat and diagnose malady.

Technical Summary

My laboratory focuses on unravelling the roles played by protein phosphorylation and ubiquitylation pathway components that emerge from the genetic analysis of human disease. In the current quinquennium the attention will be based on dissecting signalling pathways associated with Parkinson’s Disease (LRRK2), cancer (SGK3 pathway) and hypertension (WNK pathway). The aim of our research is to focus om mechanism and understand how the signalling components that we are studying are regulated and function. How mutations in these pathways disrupts biology to cause disease is also a major question. We hope to harness this information to elaborate a better understanding of human disease and to develop improved strategies to better treat and diagnose malady. For the LRRK2 research the key aims of this work are: 1. Do mutations in “Parkinson’s genes” promote LRRK2 activity and Rab protein phosphorylation? 2. Are there any specific stimuli that induce activation of LRRK2 and phosphorylation of Rab proteins? 3. How does LRRK2 mediated phosphorylation of Rab GTPases affect downstream biology? 4. Generation and use of monoclonal antibodies to better detect endogenous phosphorylation of Rab proteins by LRRK2. In parallel to this research we are working with clinicians and pharmaceutical companies with an interest in testing the therapeutic benefit of LRRK2 inhibitors for the treatment of Parkinson’s. For the SGK3 project the work will focus on studying the regulation and function of SGK3 in caner. The aims are: 1. Obtain a better understanding SGK3 biology-identification of novel SGK3 substrates in breast cancer cells; 2. How is SGK3 activated by Growth Factors. This work will help define whether SGK3 inhibitors will have therapeutic benefit for cancer. The WNK project concerns understanding how the WNK kinases that control blood pressure are regulated. This project could provide fundamental information of how cells sense and respond to osmotic and ionic stress, cellular processes that are very poorly understood.

Publications

10 25 50
 
Description Assessment of LRRK2 activity in G2385R carriers
Amount £57,771 (GBP)
Organisation Michael J Fox Foundation 
Sector Charity/Non Profit
Country United States
Start 08/2018 
End 07/2019
 
Description Chemical Screen to identify PPM1H activator
Amount £306,000 (GBP)
Organisation Michael J Fox Foundation 
Sector Charity/Non Profit
Country United States
Start 11/2019 
End 12/2020
 
Description Equipment grant
Amount £625,000 (GBP)
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start  
 
Description Equipment grant
Amount £40,000 (GBP)
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start  
 
Description Genome wide screens to uncover novel upstream regulators of LRRK2
Amount £305,944 (GBP)
Organisation Michael J Fox Foundation 
Sector Charity/Non Profit
Country United States
Start  
 
Description Impact of Shared Crohn's disease
Amount £55,444 (GBP)
Organisation Michael J Fox Foundation 
Sector Charity/Non Profit
Country United States
Start 11/2018 
End 10/2019
 
Description Lanston Award
Amount £17,582 (GBP)
Organisation Michael J Fox Foundation 
Sector Charity/Non Profit
Country United States
Start 01/2018 
End 12/2019
 
Description Project grant
Amount £95,000 (GBP)
Organisation Michael J Fox Foundation 
Sector Charity/Non Profit
Country United States
Start  
 
Description Rab LEAPs Renewal
Amount £332,000 (GBP)
Organisation Michael J Fox Foundation 
Sector Charity/Non Profit
Country United States
Start 08/2018 
End 07/2020
 
Description Tools Development
Amount £83,244 (GBP)
Organisation Michael J Fox Foundation 
Sector Charity/Non Profit
Country United States
Start 10/2018 
End 09/2020
 
Description Tools and Animal Models
Amount £54,902 (GBP)
Organisation Michael J Fox Foundation 
Sector Charity/Non Profit
Country United States
Start 07/2018 
End 12/2019
 
Description Michael J. Fox Foundation for Parkinson's Research (MJFF) Dundee Drug Discovery Unit collaborative Chemical Screens Project Grant to identify enhancer of PPM1H 
Organisation Michael J Fox Foundation
Country United States 
Sector Charity/Non Profit 
PI Contribution We identified a new protein phosphatase termed PPM1H that our work suggests that plays a key role in counteracting LRRK2 kinase activity. Our work suggests that enhancers of PPM1H activity could therefore have therapeutic benefit for Parkinson's disease. This collaborative project enables us to undertake a screen to identify such compounds.
Collaborator Contribution MJFF have provided the funding, the Dundee Drug discovery Unit are doing the enhancer screen and my lab is providing all reagents and knowledge needed to undertake the screen and will lead with the biological effects that the identified chemical activators have
Impact We have identified some enhancer compounds that we are currently characterising
Start Year 2019
 
Description Michael J. Fox Foundation for Parkinson's Research (MJFF) Dundee Drug Discovery Unit collaborative Chemical Screens Project Grant to identify enhancer of PPM1H 
Organisation University of Dundee
Department Drug Discovery Unit
Country United Kingdom 
Sector Academic/University 
PI Contribution We identified a new protein phosphatase termed PPM1H that our work suggests that plays a key role in counteracting LRRK2 kinase activity. Our work suggests that enhancers of PPM1H activity could therefore have therapeutic benefit for Parkinson's disease. This collaborative project enables us to undertake a screen to identify such compounds.
Collaborator Contribution MJFF have provided the funding, the Dundee Drug discovery Unit are doing the enhancer screen and my lab is providing all reagents and knowledge needed to undertake the screen and will lead with the biological effects that the identified chemical activators have
Impact We have identified some enhancer compounds that we are currently characterising
Start Year 2019
 
Description Attendance at the Scottish Parliament - MRC 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Policymakers/politicians
Results and Impact Myself, Professor John Rouse and Dr Paul Davies attended an event in the Scottish Parliament on 6th February to support the Medical Research Council's investment in science in Scotland and to present the work that we are doing in the MRC-PPU to MSPs.
Year(s) Of Engagement Activity 2019
 
Description Discovery may help derail Parkinson's 'runaway train 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact The press release that describes the discovery of a new enzyme called PPM1H that inhibits the LRRK2 pathway. Our data suggest that is we could get enhancers of PPM1H catalytic activity this could represent a new strategy to better treat Parkinson's disease in the future
Year(s) Of Engagement Activity 2019
URL https://www.dundee.ac.uk/news/2019/discovery-may-help-derail-parkinsons-runaway-train.php
 
Description Discussion with Health reporter from Bloomberg News 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Media (as a channel to the public)
Results and Impact I spend 1 hour on 8th July 2019 talking with Bloomberg News journalist Robert Langreth about the LRRk2 pathway and Parkinson's disease
Year(s) Of Engagement Activity 2019
 
Description Dundee Research Interest Group (DRIG) 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Patients, carers and/or patient groups
Results and Impact Myself and several members of my lab, including Dr Esther Sammler and Dr Paul Davies participated in a Parkinson's patients event organised by the Dundee Research Interest Group (DRIG) within the SLS on 18th January 2019.
Year(s) Of Engagement Activity 2019
 
Description Dundee-Edinburgh Parkinson's disease initiative 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Patients, carers and/or patient groups
Results and Impact Myself, Esther Sammler and Miratul Muqit participated in a Public event for our second Dundee-Edinburgh Parkinson's disease initiative on Friday 22nd March 2019. Over 120 patients and family members attended. I opened the session and Esther gave a presentation updating the public on research progress that has been made with Miratul participating in a panel discussion.
Year(s) Of Engagement Activity 2019
URL https://wp.me/p52H5j-5x
 
Description MRC Festical of Medical Research Inside Out Science Open Day 2018 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact MRC Festival of Medical Research Inside Out Science Open day involved researchers from the MRC Protein Phosphorylation and Ubiquitylation Unit (MRC PPU) and MRC Doctoral Training Programme students (from the Schools of Life Sciences and Medicine at the University of Dundee). The MRC Festival aimed to inform, inspire and stimulate thinking about medical research. Our event was held within the School of Life Sciences and involved seven table top engagement activities, five ten-minute accessible science talks given by PhD students and early career researchers, three lab tours and three videos about the scientific work of the Unit on loop with visitors. There were two new activities called Chromatography and Stem Cell Game trialled that were developed by MRC PPU staff and students plus previously developed activities. Prior to the open day event, a primary six class at Glebelands Primary School attended a 90 minute session to give valuable feedback on talks and new activities.

Members from my lab who participated were;
Elena Purlyte - PhD Student
Alexia Kalogeropoulou - PhD Student
Jordana Freemantle - PhD Student

Overall, 129 members of public (generally family groups) were reached with 103 people visiting on the day, a further 24 Primary Six pupils and their two teachers who gave feedback on the new talks and activities ahead of the event.
The event met a number of the objectives and key messages from the 2018 - 2023 MRC Protein phosphorylation and ubiquitination Public Engagement and Communications Plan which were:

Communications Objectives
1) Generate interest in science as a career path for young people in Dundee to reveal opportunities and make science accessible.
2) Share the unit's research expertise with non-scientific communities to raise awareness of the importance of basic research in understanding health and disease.

Key Messages
1) Basic research is vital - before we can develop new medicines we first need to understand how the body works in health and disease.
2) MRC PPU is an outstanding environment to pursue phosphorylation or ubiquitylation research.
3) As scientists we value new ideas and are open to sharing our work with all who have an interest in it.

Feedback
The visitors to the event were a mixture of ages which included family groups (children under 16 years) and adults up to 70 years of age. Feedback indicated that they enjoyed themselves overall and said they would come to a similar event again. Highlights included a game developed on the topic of Stem Cells and the laboratory tours. Around a third of visitors polled had not attended a University of Dundee event before indicating we were reaching new audiences.
The talks in particular stimulated a number of questions from the audience such as:
• How long does it take for a cell to divide?
• What would happen if you lost all your amino acids?
• Is it only older people who get Parkinson's?
• What is it about not being obese that helps protect you from Alzheimer's?
• What does wildtype mean?

Participants reported having a positive experience, they all said they'd do it again and that they'd recommend a colleague take part too.
Year(s) Of Engagement Activity 2016,2018
 
Description Meeting with Juvenescence Ltd & AI - California Life Sciences company 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact I met with Charles Roberts, the Chief Data Science Advisor of the Juvenescence Ltd & AI a California Life Science company. He is an entrepreneur who has founded numerous companies. I told him about our Units research and he was particularly interested in the work we are doing on Parkinson's disease
Year(s) Of Engagement Activity 2019
 
Description Parkinsons Fund-raisoing 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact On Wedensday 30th November I spent 1 hour talking with James Moreland and Romualda Zabityte who work for the Enotrac company about our research on LRRK2 and Parkinson's disease. Colleagues of James Moreland have undertaken a cycling race from lands end to john ogroats to raise over £5000 for our LRRK2 research. there efforts are recorded on this blog
Year(s) Of Engagement Activity 2019
URL https://www.enotrac.com/en/news/meldungen/ENOTRAC-completed-a-1000-miles-cycle-journey-across-the-UK...
 
Description Patient visit and generous donation by Kiltwalk fundraiser Moira Cardosi towards Parkinson's disease research 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Patients, carers and/or patient groups
Results and Impact Moira Cardosi, Barbara Lynch and Liz Haughey visited the MRC Protein Phosphorylation Unit to meet with myself and other members of the team to hear about our exciting research into Parkinson's disease. They also presented us with a cheque in excess of £3,000 - funds that Moira Cardosi had raised during the 2019 Kiltwalk in memory of Mrs Lynch's late husband who had suffered from the condition. During a tour of the MRC PPU laboratory our visitors also gained a first-hand impression of our work and why we believe that better understanding the causes of Parkinson's disease will eventually lead to finding a cure.
Year(s) Of Engagement Activity 2020
URL https://www.ppu.mrc.ac.uk/news/generous-donation-kiltwalk-fundraiser-moira-cardosi-towards-parkinson...
 
Description Patient/fundraiser visit Pierre and Christine Descouts 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Patients, carers and/or patient groups
Results and Impact On Friday 17th January, 2020, I met with and talked to patient/fundraiser Pierre and Christine Descouts where we discussed the research in our Unit and showed them around the laboratories. Pierre and Christine Descouts (pdescouts@hotmail.co.uk) made a personal donation of £10,000 towards Parkinson's research to the unit.
Year(s) Of Engagement Activity 2020
URL https://www.ppu.mrc.ac.uk/news/generous-ps10000-donation-christine-and-pierre-descouts-towards-esthe...
 
Description Pioneer of Digital Blood Glucose Meter Technology visits MRC-PPU 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact Professor Ian Shanks FRS and his daughter Dr Emma Shanks visited the MRC Protein Phosphorylation and Ubiquitylation Unit (PPU) on January 23rd to hear about the research being undertaken at the PPU. Ian Shanks is a pioneer of liquid crystal display (LCD) and adapted this to develop the first digital blood glucose sensor in the 1980s which has transformed the management of diabetes and benefitted millions of patients worldwide.

During their visit, they met with Dario Alessi and Miratul Muqit to hear about the latest research developments into better understanding Parkinson's disease and Philip Cohen who undertook seminal work in diabetes research to elucidate the function of insulin and delineate its signalling pathway. Finally they met with Mike Ferguson to hear how about the work of the Drug Discovery Unit and the university's links to industry.
Year(s) Of Engagement Activity 2020
URL https://www.ppu.mrc.ac.uk/news/pioneer-digital-blood-glucose-meter-technology-visits-mrc-ppu
 
Description Press Release regarding Parkinson's story 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact National media releases include; Daily Telegraph, Time, Daily Mail, Times and the Daly Telegraph
Year(s) Of Engagement Activity 2019
 
Description Solicitors Dinner - 31st October 2019 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Industry/Business
Results and Impact Myself and members of my lab, Pawel Lis and Kerryn Berndsen, showed solicitors around our lab and discussed the research that we were doing on Parkinson's disease. I participated in a video that was made to describe our Parkinson's research and attended a dinner with the solicitors that also included people with Parkinson's to explain to them our research and why it was important.
Year(s) Of Engagement Activity 2019
 
Description The Great Scottish run - Glasgow, 10k 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Other audiences
Results and Impact Myself and other members of the MRC PPU participated in the Glasgow 10K race as part of Marc van Grieken's "Shaky Team from Shaky Tou. This was to rais awareness of Parkinsons disease.
Year(s) Of Engagement Activity 2019
URL https://www.ppu.mrc.ac.uk/news/great-scottish-run-mrc-ppu-support-marc-van-griekens-fundraising-effo...
 
Description Visit from Annie MacLeod, Scotland Director for Parkinson's UKs 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Industry/Business
Results and Impact Annie MacLeod, Scotland Director for Parkinson's UK visit our lab on Thursday 7th March. The purpose of Annie's visit was to find out more about our research. Annie also had a tour of our labs as well as meeting with myself, Miratul Muqit and Esther Sammler.
Year(s) Of Engagement Activity 2019
 
Description Visit from the Scottish Chinese consulate to the MRC PPU 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Industry/Business
Results and Impact In December 2019 I welcomed Consul General Mr Qiang Ma, as well as Mr Wei Zen and Mr Wenbin Xiao, of the Consulate General of the People's Republic of China in Edinburgh to the MRC PPU where I gave them a tour of our unit and talked to them about the Chinese collaborations that our Unit has and the increasing number of Chinese staff working in our Unit. They also got the chance to meet with many Chinese MRC PPU researchers.
Year(s) Of Engagement Activity 2019
URL https://twitter.com/mrcppu/status/1207971823176032256