Identifying the predisposing genetic and dysfunctional networks through cellular models of Parkinson’s Disease.

Lead Research Organisation: Cardiff University

Abstract

Abstracts are not currently available in GtR for all funded research. This is normally because the abstract was not required at the time of proposal submission, but may be because it included sensitive information such as personal details.

Technical Summary

The UK Dementia Research Institute (UK DRI) is an initiative funded by the Medical Research Council, Alzheimer's Society and Alzheimer's Research UK. Funding details for UK DRI programmes will be added in 2019.

Parkinson’s disease (PD) is the second most common neurodegenerative disorder and results from the loss of dopaminergic neurons from the Substantia nigra pars compacta. Currently, only limited symptomatic treatments are available. Recently, iPSC-derived models of dopaminergic neurons have been developed that appear to recapitulate native dopaminergic neurons well and models derived from PD patients demonstrate face-valid dysfunction such as an increase in alpha-synuclein release.
This research programme seeks to advance our understanding of PD in three ways. Firstly, we will use single cell sequencing of iPSC-derived dopaminergic PD models to capture the gene expression pattern in each individual neuron being modelled. Through bioinformatics approaches, we can then identify dysfunctional processes and derive the order of gene expression changes through each process to better understand them. Secondly, by combining statistical genetics and gene networking approaches, we will identify both the likely causal non-coding variants within PD-risk-associated loci and the gene(s) through which these variants manifest their risk. We will then engineer iPSC-derived dopaminergic PD models to validate their disease-association. Finally, Parkinson’s patients individually vary in terms of the range of phenotypes they present, their severity and progression. To understand the molecular drivers of this variation, we have developed new methods able to derive a small number of quantitative traits that explain the much larger number of clinical observations recorded within deeply phenotyped patient cohorts. Studying these quantitative traits through statistical genetics approaches, we are able to divine the genetic drivers underlying PD patient variation which can be further investigated within our iPSC models.
Across all these three themes, the ultimate goal is to create well-understood PD-relevant cell models that are suitable for therapeutic discovery and development.

Publications

10 25 50
 
Description IM2PACT
Amount € 9,000,000 (EUR)
Funding ID 807015 
Organisation European Union 
Sector Public
Country European Union (EU)
Start 11/2018 
End 10/2023
 
Description Modelling alpha-synuclein toxicity
Amount £120,000 (GBP)
Organisation Michael J Fox Foundation 
Sector Charity/Non Profit
Country United States
Start 01/2019 
End 12/2023
 
Description Interview on BBC Radio Wales 
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 Interview discussing how scientists in Wales are at the centre of health research, this interview focused on work aimed at identifying whether people are at risk of developing dementia
Year(s) Of Engagement Activity 2018
URL https://www.bbc.co.uk/programmes/b0b9zrvv
 
Description PD UK patient forum talk 
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 I gave a PD UK patient forum talk at Waterlooville Community Centre, 10 Maurepas Way, Waterlooville, Hampshire, PO7 7AY. Wed 12/07/2017
"How can skin cells help us find therapeutics for Parkinson's?"
Year(s) Of Engagement Activity 2017
URL https://www.parkinsons.org.uk/
 
Description Parkinson's UK Research Roadshow Cardiff 
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 Public/other audiences
Results and Impact Cardiff edition of Parkinson's UK Research Roadshow took place at Hadyn Ellis Building. It was a UK wide event, inviting patients and family members to hear about exciting research taking place at specific locations and providing information on how involvement in research could help move towards better treatments and ultimately a cure. Interactive discussions with patients, carers and charity workers about 'Can stem cells find new treatments for Parkinson's'
Year(s) Of Engagement Activity 2018
URL https://www.healthandcareresearch.gov.wales/noticeboard/parkinsons-uk-research-roadshow-cardiff/?for...
 
Description Plenary Talk - ASHG2019, A single cell atlas of the human substantia nigra 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Plenary Talk, ASHG2019: A single cell atlas of the human Substantia nigra
Year(s) Of Engagement Activity 2019