Understanding Signalling Pathways Mutated in Inherited Disorders
Lead Research Organisation:
University of Dundee
Department Name: UNLISTED
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.
People |
ORCID iD |
Publications
Alessi DR
(2018)
LRRK2 kinase in Parkinson's disease.
in Science (New York, N.Y.)
Berndsen K
(2019)
PPM1H phosphatase counteracts LRRK2 signaling by selectively dephosphorylating Rab proteins.
in eLife
Bond AG
(2021)
Development of BromoTag: A "Bump-and-Hole"-PROTAC System to Induce Potent, Rapid, and Selective Degradation of Tagged Target Proteins.
in Journal of medicinal chemistry
Borsche M
(2023)
The New p. F1700L LRRK2 Variant Causes Parkinson's Disease by Extensively Increasing Kinase Activity
in Movement Disorders
Cervantes-Perez LG
(2018)
Disruption of the with no lysine kinase-STE20-proline alanine-rich kinase pathway reduces the hypertension induced by angiotensin II.
in Journal of hypertension
Conte C
(2018)
USP45 and Spindly are part of the same complex implicated in cell migration.
in Scientific reports
Di Maio R
(2018)
LRRK2 activation in idiopathic Parkinson's disease.
in Science translational medicine
Fan Y
(2021)
R1441G but not G2019S mutation enhances LRRK2 mediated Rab10 phosphorylation in human peripheral blood neutrophils.
in Acta neuropathologica
Fan Y
(2018)
Interrogating Parkinson's disease LRRK2 kinase pathway activity by assessing Rab10 phosphorylation in human neutrophils.
in The Biochemical journal
Fan Y
(2020)
Human Peripheral Blood Neutrophil Isolation for Interrogating the Parkinson's Associated LRRK2 Kinase Pathway by Assessing Rab10 Phosphorylation.
in Journal of visualized experiments : JoVE
Gomez RC
(2019)
Membrane association but not identity is required for LRRK2 activation and phosphorylation of Rab GTPases.
in The Journal of cell biology
Gordon DE
(2020)
Comparative host-coronavirus protein interaction networks reveal pan-viral disease mechanisms.
in Science (New York, N.Y.)
Hatcher J
(2023)
Development of a highly potent and selective degrader of LRRK2
in Bioorganic & Medicinal Chemistry Letters
Härtlova A
(2018)
LRRK2 is a negative regulator of Mycobacterium tuberculosis phagosome maturation in macrophages.
in The EMBO journal
Kalogeropulou AF
(2022)
Impact of 100 LRRK2 variants linked to Parkinson's disease on kinase activity and microtubule binding.
in The Biochemical journal
Kalogeropulou AF
(2020)
Endogenous Rab29 does not impact basal or stimulated LRRK2 pathway activity.
in The Biochemical journal
Karayel Ö
(2020)
Accurate MS-based Rab10 Phosphorylation Stoichiometry Determination as Readout for LRRK2 Activity in Parkinson's Disease.
in Molecular & cellular proteomics : MCP
Lis P
(2018)
Development of phospho-specific Rab protein antibodies to monitor in vivo activity of the LRRK2 Parkinson's disease kinase.
in The Biochemical journal
Liu X
(2022)
Discovery of XL01126: A Potent, Fast, Cooperative, Selective, Orally Bioavailable, and Blood-Brain Barrier Penetrant PROTAC Degrader of Leucine-Rich Repeat Kinase 2.
in Journal of the American Chemical Society
Malik AU
(2021)
Deciphering the LRRK code: LRRK1 and LRRK2 phosphorylate distinct Rab proteins and are regulated by diverse mechanisms.
in The Biochemical journal
Malik N
(2018)
Mechanism of activation of SGK3 by growth factors via the Class 1 and Class 3 PI3Ks.
in The Biochemical journal
Malik N
(2019)
Phosphoproteomics reveals that the hVPS34 regulated SGK3 kinase specifically phosphorylates endosomal proteins including Syntaxin-7, Syntaxin-12, RFIP4 and WDR44.
in The Biochemical journal
Mir R
(2018)
The Parkinson's disease VPS35[D620N] mutation enhances LRRK2-mediated Rab protein phosphorylation in mouse and human.
in The Biochemical journal
Nirujogi RS
(2021)
Development of a multiplexed targeted mass spectrometry assay for LRRK2-phosphorylated Rabs and Ser910/Ser935 biomarker sites.
in The Biochemical journal
Osborne J
(2019)
Discovery of potent and selective 5-azaindazole inhibitors of leucine-rich repeat kinase 2 (LRRK2) - Part 1
in Bioorganic & Medicinal Chemistry Letters
Ostrosky-Frid M
(2021)
Role of KLHL3 and dietary K+ in regulating KS-WNK1 expression.
in American journal of physiology. Renal physiology
Purlyte E
(2019)
Rab29 activation of the Parkinson's disease-associated LRRK2 kinase.
in The EMBO journal
Purlyte E
(2018)
Rab29 activation of the Parkinson's disease-associated LRRK2 kinase.
in The EMBO journal
Rihn SJ
(2021)
A plasmid DNA-launched SARS-CoV-2 reverse genetics system and coronavirus toolkit for COVID-19 research.
in PLoS biology
Tasegian A
(2021)
Impact of Type II LRRK2 inhibitors on signaling and mitophagy.
in The Biochemical journal
Taylor M
(2020)
Advances in elucidating the function of leucine-rich repeat protein kinase-2 in normal cells and Parkinson's disease.
in Current opinion in cell biology
Tovell H
(2019)
Design and Characterization of SGK3-PROTAC1, an Isoform Specific SGK3 Kinase PROTAC Degrader.
in ACS chemical biology
Tovell H
(2019)
Rapid and Reversible Knockdown of Endogenously Tagged Endosomal Proteins via an Optimized HaloPROTAC Degrader.
in ACS chemical biology
Vagnarelli P
(2018)
PP1 Phosphatase Complexes: Undruggable No Longer.
in Cell
Vides EG
(2022)
A feed-forward pathway drives LRRK2 kinase membrane recruitment and activation.
in eLife
Wang J
(2018)
Structural and Atropisomeric Factors Governing the Selectivity of Pyrimido-benzodiazipinones as Inhibitors of Kinases and Bromodomains.
in ACS chemical biology
Waschbüsch D
(2021)
Structural basis for the specificity of PPM1H phosphatase for Rab GTPases.
in EMBO reports
Waschbüsch D
(2020)
Structural Basis for Rab8a Recruitment of RILPL2 via LRRK2 Phosphorylation of Switch 2.
in Structure (London, England : 1993)
Zhang P
(2019)
Crystal structure of the WD40 domain dimer of LRRK2.
in Proceedings of the National Academy of Sciences of the United States of America
Related Projects
| Project Reference | Relationship | Related To | Start | End | Award Value |
|---|---|---|---|---|---|
| MC_UU_00018/1 | 01/04/2018 | 31/03/2024 | £4,394,000 | ||
| MC_UU_00018/2 | Transfer | MC_UU_00018/1 | 01/04/2018 | 31/03/2024 | £2,542,000 |
| MC_UU_00018/3 | Transfer | MC_UU_00018/2 | 01/04/2018 | 31/03/2024 | £3,121,000 |
| MC_UU_00018/4 | Transfer | MC_UU_00018/3 | 01/04/2018 | 31/03/2024 | £2,751,000 |
| MC_UU_00018/5 | Transfer | MC_UU_00018/4 | 01/04/2018 | 31/03/2024 | £3,744,000 |
| MC_UU_00018/6 | Transfer | MC_UU_00018/5 | 01/04/2018 | 31/03/2024 | £2,520,000 |
| MC_UU_00018/7 | Transfer | MC_UU_00018/6 | 01/04/2018 | 31/03/2024 | £2,557,000 |
| MC_UU_00018/8 | Transfer | MC_UU_00018/7 | 01/04/2018 | 31/03/2024 | £2,128,000 |
| Description | 4 x MRC UKRI DRI Small Research Grants (Co-Investigator) |
| Amount | £20,000 (GBP) |
| Organisation | Medical Research Council (MRC) |
| Sector | Public |
| Country | United Kingdom |
| Start | |
| Description | Accelerating drug discovery in the cell signalling system |
| Amount | £7,500,000 (GBP) |
| Organisation | Medical Research Council (MRC) |
| Sector | Public |
| Country | United Kingdom |
| Start | 06/2020 |
| 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 | £1,200,000 (GBP) |
| Organisation | Medical Research Council (MRC) |
| Sector | Public |
| Country | United Kingdom |
| Start | 01/2020 |
| Description | Equipment grant |
| Amount | £625,000 (GBP) |
| Organisation | Medical Research Council (MRC) |
| Sector | Public |
| Country | United Kingdom |
| Start | |
| Description | Equipment grant |
| Amount | £808,000 (GBP) |
| Organisation | Medical Research Council (MRC) |
| Sector | Public |
| Country | United Kingdom |
| Start | 04/2020 |
| 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 | LRRK2 biology investigation |
| Amount | £62,000 (GBP) |
| Organisation | Michael J Fox Foundation |
| Sector | Charity/Non Profit |
| Country | United States |
| Start | 02/2020 |
| 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 | MJFF (Lead Investigator) Andy Howden |
| Amount | £282,582 (GBP) |
| Funding ID | MJFF-020421 |
| Organisation | Michael J Fox Foundation |
| Sector | Charity/Non Profit |
| Country | United States |
| Start | |
| Description | MJFF (Lead Investigator) Project Grant |
| Amount | £49,281 (GBP) |
| Funding ID | MJFF-019894 |
| Organisation | Michael J Fox Foundation |
| Sector | Charity/Non Profit |
| Country | United States |
| Start | |
| Description | MJFF PPM1H activator grant (Lead Investigator |
| Amount | £642,000 (GBP) |
| Funding ID | MJFF-021159 |
| Organisation | Michael J Fox Foundation |
| Sector | Charity/Non Profit |
| Country | United States |
| Start | |
| Description | MRC Portfolio Review Award, Supporting MRC to make reagents from its Units and Institutes available, |
| Amount | £80,000 (GBP) |
| Organisation | Medical Research Council (MRC) |
| Sector | Public |
| Country | United Kingdom |
| Start | 12/2020 |
| Description | MRC Response Award, Covod-19 toolbox project |
| Amount | £250,000 (GBP) |
| Organisation | Medical Research Council (MRC) |
| Sector | Public |
| Country | United Kingdom |
| Start | 11/2020 |
| Description | MRC UKRI DRI Proteomics Project Award (Lead Investigator) |
| Amount | £287,000 (GBP) |
| Funding ID | DRI-PROT2021-DUN |
| Organisation | Medical Research Council (MRC) |
| Sector | Public |
| Country | United Kingdom |
| Start | |
| Description | MRC UKRI World Class Labs (Lead Investigator) Cryo-EM contribution |
| Amount | £350,000 (GBP) |
| Organisation | Medical Research Council (MRC) |
| Sector | Public |
| Country | United Kingdom |
| Start | |
| Description | MRC UKRI World Class Labs (Lead Investigator) Equipment |
| Amount | £100,000 (GBP) |
| Organisation | Medical Research Council (MRC) |
| Sector | Public |
| Country | United Kingdom |
| Start | |
| 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 | Regulation and function of LRRK2 |
| Amount | £6,150,000 (GBP) |
| Organisation | Aligning Sciences Across Parkinson's |
| Sector | Charity/Non Profit |
| Country | United States |
| Start | 09/2020 |
| Description | Regulation of AMPK by protein phosphatases |
| Amount | £376,000 (GBP) |
| Organisation | Novo Nordisk Foundation |
| Sector | Charity/Non Profit |
| Country | Denmark |
| Start | 05/2020 |
| Description | Role of LRRK2 in inflammatory bowl disease |
| Amount | £99,000 (GBP) |
| Organisation | Tenovus Cancer Care |
| Department | Tenovus Scotland |
| Sector | Charity/Non Profit |
| Country | United Kingdom |
| Start | 03/2020 |
| 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 | Aligning Science Across Parkinson's: ASAP to probe LRRK2 biology |
| Organisation | Aligning Sciences Across Parkinson's |
| Country | United States |
| Sector | Charity/Non Profit |
| PI Contribution | I have set up a new collaborative team consisting of Miratul Muqit (University of Dundee), Suzanne Pfeffer and Monther Abu Remaileh (both Stanford University) to better study the biology of a protein kinase termed LRRK2 that is linked to Parkinson's. I am the team leader for this collaboration and coordinated the grant writing and project when it initiated in September 2020 |
| Collaborator Contribution | My lab undertake the mechanistic, biochemical and mass spectroscopy analysis, Miratul Muqit lab studies how PINK1 and LRRK2 impact the mitochondria, Monther Abu Remaileh has set up a new method to isolate lysosomes and Suzanne Pfeffer undertakes the cell biology part of the project The ASAP award will allow the Alessi and Muqit labs to embark on one of the biggest initiatives in history to accelerate understanding of the origins of Parkinson's disease, embracing high quality and fully open and interdisciplinary collaboration. It is also a major step towards our goal of creating a leading Parkinson's Research Centre at the University of Dundee. This ASAP-initiative award will enable us recruit and fund ~10 postdocs and 2 PhD students. |
| Impact | Collaboration is multi-disciplinary involving biochemical, physiology and cellular studies |
| Start Year | 2020 |
| 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 | Renewal of DSTT Collaboration (2020-2024) |
| Organisation | Boehringer Ingelheim |
| Department | Boehringer Ingelheim |
| Country | Canada |
| Sector | Private |
| PI Contribution | This unique collaboration between scientists at the University of Dundee and pharmaceutical companies, is dedicated to accelerating the development of specific inhibitors and chemical probes that target protein phosphorylation and ubiquitylation systems, and also to advance the study of cell signalling. This is one of the worlds longest industrial-academic collaborations have been running since 1998. The current companies in the collaboration are GlaxoSmithKline, Merck-KGA and Boehringer Ingelheim. 23 different research groups at the University of Dundee participate in this collaboration. The current renewal grant was £7.5 million |
| Collaborator Contribution | I am the Director of this collaboration and coordinate the interactions between the pharmaceutical companies and the Dundee academic labs. The pharmaceutical companies and our research laboratories select research projects based on their complementary interests and expertise. The aim of the work is to undertake research projects that accelerate the drug discovery process in the field of cell signalling |
| Impact | Dozens of publications have resulted from this award and we have contributed to industrial research from our partners that have led to several new approved drugs |
| Description | Renewal of DSTT Collaboration (2020-2024) |
| Organisation | GlaxoSmithKline (GSK) |
| Country | Global |
| Sector | Private |
| PI Contribution | This unique collaboration between scientists at the University of Dundee and pharmaceutical companies, is dedicated to accelerating the development of specific inhibitors and chemical probes that target protein phosphorylation and ubiquitylation systems, and also to advance the study of cell signalling. This is one of the worlds longest industrial-academic collaborations have been running since 1998. The current companies in the collaboration are GlaxoSmithKline, Merck-KGA and Boehringer Ingelheim. 23 different research groups at the University of Dundee participate in this collaboration. The current renewal grant was £7.5 million |
| Collaborator Contribution | I am the Director of this collaboration and coordinate the interactions between the pharmaceutical companies and the Dundee academic labs. The pharmaceutical companies and our research laboratories select research projects based on their complementary interests and expertise. The aim of the work is to undertake research projects that accelerate the drug discovery process in the field of cell signalling |
| Impact | Dozens of publications have resulted from this award and we have contributed to industrial research from our partners that have led to several new approved drugs |
| Description | Renewal of DSTT Collaboration (2020-2024) |
| Organisation | Merck |
| Department | Merck Serono |
| Country | Germany |
| Sector | Private |
| PI Contribution | This unique collaboration between scientists at the University of Dundee and pharmaceutical companies, is dedicated to accelerating the development of specific inhibitors and chemical probes that target protein phosphorylation and ubiquitylation systems, and also to advance the study of cell signalling. This is one of the worlds longest industrial-academic collaborations have been running since 1998. The current companies in the collaboration are GlaxoSmithKline, Merck-KGA and Boehringer Ingelheim. 23 different research groups at the University of Dundee participate in this collaboration. The current renewal grant was £7.5 million |
| Collaborator Contribution | I am the Director of this collaboration and coordinate the interactions between the pharmaceutical companies and the Dundee academic labs. The pharmaceutical companies and our research laboratories select research projects based on their complementary interests and expertise. The aim of the work is to undertake research projects that accelerate the drug discovery process in the field of cell signalling |
| Impact | Dozens of publications have resulted from this award and we have contributed to industrial research from our partners that have led to several new approved drugs |
| Title | BromoTag |
| Description | This relates to the contribution our lab has made to the development of the BromoTag that can be added to any protein to induce is degradation following addition of a degrader compound such as AGB1 |
| IP Reference | PCT/GB2022/052408 |
| Protection | Patent / Patent application |
| Year Protection Granted | 2023 |
| Licensed | Yes |
| Impact | This technology is now being widely used as one of the main approaches to lower protein expression in a conditional manner |
| Title | Discovery of LRKK2 degrsders that might have theraputic potential for Parkinson's and inflammatory bowel disease |
| Description | Leucine-rich repeat kinase 2 (LRRK2), encoded by LRRK2 gene, is a large (286 kDa), multi-domain protein. The armadillo repeat motif (ARM), ankyrin repeat domain (ANK), leucine-rich repeat domain and the WD40 repeat domain are involved in protein-protein interactions; the Ras of complex protein (ROC) and C terminus of ROC (COR) tandem domain functions as GTPase; the most-studied kinase domain of LRRK2 is responsible for autophosphorylation at Ser-1292 (Sheng et al., 2012) and phosphorylating a group of Rab GTPases that are involved in vesicle trafficking (Steger et al., 2016). LRRK2 is found to play roles in both sporadic PD and familial PD (Tolosa et al., 2020). Pathological mutations in the RocCOR GTPase domain (R1441C/G/H, N1437H, Y1699C) and the kinase domain (G2019S, I2020T) result in altered GTPase and/or kinase activity, leading to functional alterations in vesicular trafficking, cytoskeleton dynamics, autophagy, lysosomal degradation, neurotransmission, mitochondrial function and many other pathogenic hallmarks associated with PD (Tolosa et al., 2020). Targeting the GTPase and kinase activities of LRRK2 are therefore considered as potential disease-modifying PD therapies (Tolosa et al., 2020), with numerous LRRK2 kinase inhibitors described in the past, including LRRK2-IN-1 (Deng et al., 2011), HG-10-102-01 (Choi et al., 2012), MLi-2 (Fell et al., 2015), PF-06447475 (Henderson et al., 2015), and DNL201 and DNL151 which are the first two LRRK2 kinase inhibitors in clinical trial (Tolosa et al., 2020). However, all these LRRK2 kinase inhibitors are ATP-competitive type 1 kinase inhibitors which enhance LRRK2 mislocalization and microtubule association by preferably binding to the open conformation of LRRK2 (Deniston et al., 2020; Watanabe et al., 2020), underlying undesirable effects on vesicular tra?cking and the on-target side-effects observed on lung and kidney (Andersen et al., 2018; Baptista et al., 2020). Type 1 inhibitors also induce dephosphorylation of LRRK2 at a cluster of phosphorylation sites surrounding Ser935 that may be undesirable (PMID 34515301). Alternative LRRK2 targeting strategies, such as G2019S LRRK2 selective inhibitors (Garofalo et al., 2020; Lesniak et al., 2022), LRRK2 dimerization inhibitors (Helton et al., 2021), GTPase inhibitors, antisense oligonucleotide, type 2 LRRK2 kinase inhibitors (Tasegian et al., 2021), and LRRK2 proteolysis targeting chimeras (PROTACs) (Konstantinidou et al., 2021) (WO2020081682A1 and WO 02020081682A1) have therefore been proposed and explored. |
| IP Reference | EP22386025.5 |
| Protection | Patent / Patent application |
| Year Protection Granted | 2023 |
| Licensed | No |
| Impact | We are exploring further work with industrial partners |
| 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 | COVID-19 research being carried out by the MRC-PPU |
| Form Of Engagement Activity | A broadcast e.g. TV/radio/film/podcast (other than news/press) |
| Part Of Official Scheme? | No |
| Geographic Reach | National |
| Primary Audience | Media (as a channel to the public) |
| Results and Impact | Press release on COVID-19 research being carried out by the MRC-PPU in conjunction with Glasgow's VRC was picked up by several newspapers, including the i, Daily Record, Daily Mail, Herald, Courier, Evening Telegraph, Evening Times, and National. I spent much of Monday 30th March in personal interviews (via skype) to Reporting Scotland, Good Morning Scotland, STV, Radio Tay, BBC, BBC Radio, Daily Telegraph and Wave FM. |
| Year(s) Of Engagement Activity | 2020 |
| URL | https://www.dundee.ac.uk/stories/universities-join-forces-help-pandemic-fight |
| Description | Connect and collaborate Parkinson's outreach event in the School of Life Sciences |
| 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 | Patients, carers and/or patient groups |
| Results and Impact | On November 7 of this year, the chief executive team of Parkinson's UK including CEO Caroline Rassell, Deputy director of research Professor David Dexter and the new Scotland director James Jopling visited the Parkinson's research team at the University of Dundee. In the morning, researchers from Dundee including Professor Dario Alessi, Dr. Paul Davies, ProfessorMiratul Muqit, Dr. Andy Howden, Professor Ian Ganley and Dr. Esther Sammler, from Aberdeen Professor Bettina Platt and Julie Jones, from St. Andrews Doris Chen and from Edinburgh, Professor Tilo Kunath gave an overview of their work. |
| Year(s) Of Engagement Activity | 2022 |
| 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 | Interview for the Sunday Post |
| 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 | Media (as a channel to the public) |
| Results and Impact | I gave an interview for the Sunday Post where the questions "Should we wash our shopping? Wear a mask to the shops? Use a lift? Well, what do the scientists do?" were asked. |
| Year(s) Of Engagement Activity | 2020 |
| URL | https://www.sundaypost.com/fp/should-we-wash-our-shopping-wear-a-mask-to-the-shops-use-a-lift-well-w... |
| Description | Interview with Journalist 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 | Public/other audiences |
| Results and Impact | On Thursday 19th January, I spent ~90 minutes talking with Robert Langreth, a Journalist from Bloomberg News, on the subject of Pakrinson disease, Alzheimer's and other neurological diseases. Robert was looking to write a story on where the efforts for parkinson's disease modifying drugs stand. Robert was interested in finding out more about lrrk2 and parkinson's disease research. Robert advised he had also spoken with the MJFF and ASAP re how the influx of funding from MJFF/Sergey Brin/Asap is changing things, and how is the approach taken in parkinson's differ from the more single minded focus in Alzheimer's. |
| Year(s) Of Engagement Activity | 2023 |
| Description | Lunch with a family who has been affected by Parkinson's disease |
| 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 | Public/other audiences |
| Results and Impact | In September 2020 I attended a lunch with a family affected with Parkinson's disease and discussed with them the research that was on-going and how they could support this. |
| Year(s) Of Engagement Activity | 2020 |
| 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 | Meeting with UoD alumni |
| Form Of Engagement Activity | Participation in an activity, workshop or similar |
| Part Of Official Scheme? | No |
| Geographic Reach | Local |
| Primary Audience | Other audiences |
| Results and Impact | Myself, and other members of SLS, participated in an event which welcomed medics who graduated from Dundee University in 1977. I discussed with them the current research that is taking place in our Unit and beyond in Dundee. |
| Year(s) Of Engagement Activity | 2022 |
| 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 | 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 | Provided written evidence to the HoC Scottish Affairs Committee |
| Form Of Engagement Activity | A talk or presentation |
| Part Of Official Scheme? | No |
| Geographic Reach | National |
| Primary Audience | Policymakers/politicians |
| Results and Impact | I, along with Wendy Bickmore the Director of the HGU MRC Unit-in Edinburgh, contributed to a consultation letter to the HoC Scottish Affairs Committee explaining the importance of UKRI MRC investment in supporting medical research in Scotland |
| Year(s) Of Engagement Activity | 2020 |
| URL | https://committees.parliament.uk/writtenevidence/12622/pdf/ |
| Description | Pursuing a breakthrough for Parkinson's |
| Form Of Engagement Activity | A magazine, newsletter or online publication |
| Part Of Official Scheme? | No |
| Geographic Reach | National |
| Primary Audience | Media (as a channel to the public) |
| Results and Impact | Pursuing a breakthrough for Parkinson's |
| Year(s) Of Engagement Activity | 2021 |
| URL | https://www.dundee.ac.uk/stories/pursuing-breakthrough-parkinsons |
| Description | Rallying to the Challenge - a general discussion |
| Form Of Engagement Activity | A talk or presentation |
| Part Of Official Scheme? | No |
| Geographic Reach | International |
| Primary Audience | Patients, carers and/or patient groups |
| Results and Impact | On Wednesday 8th September, myself, Miratul Muqit and Esther Sammler held a recorded a general discussion with Marc Van Greiken and Helen Matthews for the Cure Parkinson's trust on the research that we are doing in Dundee. This talk will be shown at a special 2021 conference for people with Parkinson's called "Rallying" that will have a worldwide audience. Rallying is a meeting for people with Parkinson's with the agenda designed by and with people living with Parkinson's. It is based on the Grand Challenges which were in person meetings held at the Van Andel Institute in Michigan. |
| Year(s) Of Engagement Activity | 2021 |
| URL | https://cureparkinsons.org.uk/rallying-to-the-challenge-2021/ |
| Description | Reception at the house of Lords in London |
| Form Of Engagement Activity | A talk or presentation |
| Part Of Official Scheme? | No |
| Geographic Reach | National |
| Primary Audience | Policymakers/politicians |
| Results and Impact | On Monday 14th March 20202 I attended a reception at the house of Lords in London which was hosted by the "All-Party Parliamentary Group on Medical Research, to discuss Tackling COVID-19: Recognising the exceptional research response". I talked to various MPs who attended the event about our research and the importance of medical research in the UK today and discussed the work that the MRC-PPU undertook to support the UK Covid-response research efforts." |
| Year(s) Of Engagement Activity | 2022 |
| 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 |