Exploring the therapeutic potential of Rab GTPases in Parkinson's disease

Lead Research Organisation: University of Leicester
Department Name: Genetics

Abstract

Parkinson's disease (PD), the second most common neurodegenerative disorder, is characterized by loss of dopaminergic neurons and the accumulation of misfolded synuclein (aSyn). Aberrant aSyn aggregation and consequent perturbed vesicular trafficking likely contribute to neurodegeneration. Rab GTPases play critical roles in vesicular trafficking in the cell, and have been implicated in the pathogenesis of PD. We have found that both Rab11 and Rab8a can strongly suppress disease phenotypes in models of PD. However, systematic testing of the 60 Rab family members in PD models has not been performed, and therapeutic strategies targeting these proteins are lacking. We recently performed a siRNA screen targeting Rab GTPase genes in mammalian cells to identify genes which modulate aSyn aggregation. We identified 22 genes, a subset of which will be investigated in this project. The student will assess modulation of aSyn-dependent disease-related phenotypes by candidate Rabs using biochemical and microscopy approaches. Alterations in synaptic vesicular release and Rab localisation due to aSyn will be examined using fluorescence and ultrastructural imaging of synaptic vesicles in neurons. The effects of Rabs upon aSyn disease phenotypes in Drosophila will also be examined. This work will provide important insight into the mechanisms and therapeutic potential of Rab GTPases in PD.

Publications

10 25 50
 
Description Unravelling the role of RAB39B in Parkinson's disease pathogenesis
Amount £264,522 (GBP)
Funding ID G-1802 
Organisation Parkinson's UK 
Sector Charity/Non Profit
Country United Kingdom
Start 02/2019 
End 02/2022
 
Description Collaboration with Prof Dr Tiago F Outeiro 
Organisation University of Göttingen
Department Department of Neurodegeneration and Restaurative Research
Country Germany 
Sector Academic/University 
PI Contribution The collaboration with Prof Dr Tiago Outeiro, Director of the Department of NeuroDegeneration and Restaurative Research, began in 2006, and has consisted of several projects related to Parkinson's and Huntington's disease. During this time we have co-supervised 4 PhD students and 2 postdoctoral fellows, and received funding from several grant applications. Prior to our collaboration, the research in my lab was focused primarily upon Huntington's disease, while Prof Dr Outeiro had great expertise in Parkinson's disease, but limited experience with Huntington's disease. During this collaboration my research time has provided contributions in the collaboration regarding the use and analysis of genetic models.
Collaborator Contribution We have gained from Prof Dr Outeiro's expertise in models of Parkinson's disease, which has allowed us to successfully expand our research into this area. This has been quite important, as several of our areas of interest in neurodegeneration are common between Huntington's disease and Parkinson's disease, and we are now addressing these issues in Parkinson's as well. Our collaboration has recently been strengthened and extended by work on Rab39 funded by Parkinson's UK, as well as studentship funded by the MRC through the MRC Impact DTP.
Impact PUBLICATIONS: Breda C, Nugent ML, Estranero JG, Kyriacou CP, Outeiro TF, Steinert JR, Giorgini F*. Rab11 modulates a-synuclein mediated defects in synaptic transmission and behaviour. Hum Mol Genet 2014 Oct 9. pii: ddu521. [Epub ahead of print]. Chutna O, Gonçalves S, Villar-Piqué A, Guerreiro P, Marijanovic Z, Mendes T, Ramalho J, Emmanouilidou E, Ventura S, Klucken J, Barral DC, Giorgini F, Vekrellis K, Outeiro TF. The small GTPase Rab11 co-localizes with a-synuclein in intracellular inclusions and modulates its aggregation, secretion and toxicity. Hum Mol Genet, 2014 Aug 4. pii: ddu391. [Epub ahead of print]. Zondler L, Miller-Fleming L, Repici M, Gonçalves S, Tenreiro S, Rosado-Ramos R, Betzer C, Straatman KR, Henning Jensen P, Giorgini F*, Outeiro TF*. DJ-1 interactions with a-synuclein attenuate aggregation and cellular toxicity in models of Parkinson's disease. Cell Death Dis, 2014; 5: e1350. Yin G, Lopes da Fonseca T, Eisbach SE, Martín Anduaga A, Breda C, Karpinar DP, Orcellet ML, Szego EM, Guerreiro P, Lazaro D, Braus GH , Fernandez CO, Griesinger C, Becker S, Goody RS, Itzen A, Giorgini F, Outeiro TF, Zweckstetter M. alpha-Synuclein interacts with the switch region of Rab8a in a Ser129 phosphorylation-dependent manner. Neurobiology of Disease, 2014 Jun 28. [Epub ahead of print]. Miller-Fleming L, Antas P, Faria Pais T, Smalley JL, Giorgini F*, Outeiro TF*. Yeast DJ-1 family members are required for diauxic-shift reprogramming and cell survival in stationary phase. PNAS, 2014; 111(19): 7012-7. Vittori A, Breda C, Repici M, Orth M, Roos RAC, Outeiro TF, Giorgini F*, Hollox EJ* and the REGISTRY investigators of the European Huntington's Disease Network. Copy number variation of the neuronal glucose transporter gene SLC2A3 modifies the age of onset in Huntington's disease. Hum Mol Genet, 2014; 23(12): 3129-37. Sajjad MU, Green EW, Miller-Fleming L, Hands S, Herrera F, Campesan S, Khoshnan A, Outeiro TF, Giorgini F, Wyttenbach A. DJ-1 modulates aggregation and pathogenesis in models of Huntington's disease. Hum Mol Genet, 2014; 23(3): 755-766. Amaral M, Outeiro TF, Scrutton NS, Giorgini F*. The causative role and therapeutic potential of the kynurenine pathway in neurodegenerative disease. J Mol Med, 2013; 91(6): 705-13. Amaral M, Levy C, Heyes DJ, Lafite P, Outeiro TF, Giorgini F, Leys D, Scrutton NS. Structural basis of kynurenine 3-monooxygenase inhibition. Nature, 2013; 496(7445):382-5. Repici M, Straatman KR, Enguita F, Outeiro TF, Giorgini F. Mutations in DJ-1 differentially modulate dimerization in living cells. J Mol Med, 2012 Nov 27. [Epub ahead of print]. Tauber E, Miller-Fleming L, Mason RP, Kwan W, Clapp J, Butler NJ, Outeiro TF, Muchowski PJ, Giorgini F. Functional gene expression profiling in yeast implicates translational dysfunction in mutant huntingtin toxicity. J Biol Chem 2011; 286(1):410-9. Miller-Fleming L, Giorgini F, Outeiro TF. Yeast as a Model for Studying Human Neurodegenerative Disorders. Biotechnol J 2008; 3(3): 325-38. GRANTS: 1) Project Grant - Giorgini (PI), Kyriacou (Co-PI), Outeiro (Project Partner) 01/12/2013 - 11/30/2016 Medical Research Council - MR/L003503/1 £ 460,100 "DJ-1 and neurodegeneration: its roles in mitochondria and in protein misfolding" 2) Next Step Funding - Giorgini (PI), Outeiro (Co-PI) 01/12/2012 - 31/12/2013 Parkinson's UK - G-0902 £ 19,919 "Deciphering the molecular role of DJ-1 in the etiology of Parkinson's disease-Next Step Funding" 3) Project Grant - Giorgini (PI), Outeiro (Co-PI) 01/04/2012 - 30/09/2013 Parkinson's UK - G-1203 £ 92,959 "Unravelling the pathogenic role and therapeutic potential of Rab family GTPases in Parkinson's" 4) Project Grant - Giorgini (PI), Outeiro (Co-PI) 01/10/2009 - 30/11/2012 Parkinson's UK - G-0902 £ 242,759 "Deciphering the molecular role of DJ-1 in the etiology of Parkinson's disease"
Start Year 2006
 
Description GENIE- Dyamic DNA school outreach event 
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 Schools
Results and Impact Dynamic DNA is an outreach event for ~600 Year 9 students from Leicestershire schools. This involves working with small groups to engage the children in science in a fun and exciting way using experiments, where possible, or using props to replicate scientific techniques and explain topics that they learn as part of the curriculum but also new areas. One of the experiments I run for the children involves them carrying out an experiment, similar in design to what I use regularly for my project, that measures locomotor ability in fruit flies related to neurodegenerative symptoms observed in Parkinson's disease. This enabled the children to see some of the ways scientists explore diseases that they were previously unaware of, the fun nature of the day encourages children who enjoy science to ask questions about a career in research.
Year(s) Of Engagement Activity 2017,2018
URL https://www2.le.ac.uk/projects/genie/outreach/dynamic-dna
 
Description Invited seminar, Department of Neuroscience, Psychology and Behaviour, University of Leicester, UK. 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Professional Practitioners
Results and Impact This was a departmental seminar at the University of Leicester, with approximately 30 participants, including other academics, postdoctoral researchers and postgraduate students. The talk sparked questions and discussion, and the possibility of new collaboration.
Year(s) Of Engagement Activity 2020
 
Description Panel member for a webinar with Parkinson's patients 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Patients, carers and/or patient groups
Results and Impact Myself and supervisor took part in an evening event organised by the Leicester Early onset Parkinson's disease group, we were the local research members for a panel, which also included other Parkinson's researchers/clinicians that were linked via webchat from Australia and other countries. The purpose of the webinar was to enable patients and carers worldwide to ask experts in the field questions about the research that was of importance to them. We talked about the work we do in our lab, discussed the major studies happening in the field as well as clinical trials and issues with funding. It was a really enjoyable evening for everyone involved and highlighted the importance of communication between clinicians, patients and researchers for progression of treatments for patients.
Year(s) Of Engagement Activity 2018
 
Description Parkinson's UK Project Engagement Volunteer (PEV) Scheme 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Patients, carers and/or patient groups
Results and Impact As part of the new Patient Engagement Volunteer (PEV) Scheme being trialled by Parkinson's UK our lab group invited patients and family members of a Midlands volunteer group to visit the lab. The day involved a discussion about how they could be more involved with our lab and how we could upate them regularly on the progress of the project/other events. I gave a talk giving an overview of the rab39 work showing our results and progress so far. Other members of the lab also gave rab relevant talks for other neurodegenerative studies happening in our lab. The volunteers were given tours of the lab and had the opportunity to see the work we carry out firsthand.
Year(s) Of Engagement Activity 2019
URL https://eastmidlands-rsn.org/2019/12/31/east-midlands-project-engagement-meeting-investigating-the-r...
 
Description Talk at Parkinson's Conference for Women 
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 The conference was organised for women with Parkinson's disease, it included a variety of discussion/debates and talks between researchers, healthcare professionals, clinicians and patients.

I was able to discuss my rab39 research with the patients who were all interested in how fruit flies can be used in the lab and the possible progression into more clinical relevant research. As well as this I gave a talk to highlight the importance of female participation in all areas of science to encourage more women to be involved in science somehow if they are given the chance, I also used my research journey as an example for why women should think about a career in research. By the end of the day the audience were familiar with the lab work I have been doing, as well as how gender bias can affect the outcome of clinical research.
Year(s) Of Engagement Activity 2019
URL https://www.parkinsons.org.uk/events/parkinsons-eve
 
Description Talk at the Eighth Annual East Midlands Research Support Network Forum, Parkinson's UK, Link Hotel, Loughborough, UK; "The genetics of Parkinson's" 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Patients, carers and/or patient groups
Results and Impact ~100 PD patients/carers/patient groups members attended this Parkinson's UK event organised by the East MIdlands branch, where i gave a talk on PD genetics and some of our research funded by Parkinson's. The talk led to questions afterwards from some participants.
Year(s) Of Engagement Activity 2019
 
Description Talk at the Parkinson's East Midlands Research Support Network, 7th Researchers Meeting, MRC Toxicology Unit, Leicester, UK ; "Unravelling the role of RAB39B in Parkinson's" 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Patients, carers and/or patient groups
Results and Impact ~20 people involved in the East Midlands Research Support network attended the event, which included talks from several Parkinson's researchers across the UK. I gave a talk providing an overview of our recently funded Parkinson's UK grant, and had questions afterwards from the audience.
Year(s) Of Engagement Activity 2019