Multiscale modelling of progression in Parkinson's disease
Lead Research Organisation:
University College London
Department Name: Institute of Neurology
Abstract
Parkinson's disease (PD) is an incurable neurodegenerative condition affecting over ten million people worldwide. It is highly variable in presentation and progression, and whilst disease subtypes have been described at both the clinical and molecular scale, how these relate to one another remain poorly understood. To bridge this gap, we will map the mechanisms of disease progression in PD across multiple biological scales, from cells to circuits, in the same individuals. We will develop a multiscale generative model to characterise how pathophysiological mechanisms interact within and between different levels and allow us to ask how these processes result in the observed clinical syndrome. This proposal would be impossible to achieve working independently, and hinges on a synergistic collaboration between molecular, cellular, clinical and computational neuroscience. It will develop a framework to allow disease types to be defined by their cause, rather than their phenotype, and provide a platform to help dissect mechanistic pathways across scale, and more rapidly develop precision therapies. Delivering tools to integrate data across scale in the same individuals, our vision is to provide an accessible framework, applicable to many other disorders, to allow more rapid translation of targeted treatments that can be started before irreversible loss of tissue has occurred.
Technical Summary
Disease progression is a key feature of PD, defined in terms of pathology within a brain region (c.f., symptom severity) and the spread of pathology between regions (c.f., new symptoms). Progression is highly variable, and potential mechanisms span many biological scales: with differences in where the disease begins, pattern of damage across circuits, co-existing pathologies, abnormal neural dynamics, cellular vulnerability and organelle dysfunction all thought to contribute.
This project aims to map the mechanisms of disease progression in Parkinson's disease (PD) across multiple biological scales, from cells to circuits, in the same individuals. Framing PD progression as differences in the cortical burden of disease (cortical dominant = fast; brainstem dominant = slow), we will identify individuals with extreme phenotypes of progression from an existing cohort to:
(i) Define longitudinal changes in brain microstructure in vivo.
(ii) Map the molecular and cellular dynamics using in vitro human models from the same individuals.
(iii) We will integrate data (i) and (ii) to inform a deep generative model, where mechanisms at one scale-quantified via model parameters derived from experimental measures-provide information used by the next. This will characterise how these pathophysiological mechanisms at different scales interact to result in the clinical syndrome observed.
This program will deliver an open framework of integrated resources that can then be used in a translational setting.
This project aims to map the mechanisms of disease progression in Parkinson's disease (PD) across multiple biological scales, from cells to circuits, in the same individuals. Framing PD progression as differences in the cortical burden of disease (cortical dominant = fast; brainstem dominant = slow), we will identify individuals with extreme phenotypes of progression from an existing cohort to:
(i) Define longitudinal changes in brain microstructure in vivo.
(ii) Map the molecular and cellular dynamics using in vitro human models from the same individuals.
(iii) We will integrate data (i) and (ii) to inform a deep generative model, where mechanisms at one scale-quantified via model parameters derived from experimental measures-provide information used by the next. This will characterise how these pathophysiological mechanisms at different scales interact to result in the clinical syndrome observed.
This program will deliver an open framework of integrated resources that can then be used in a translational setting.
Publications
![publication icon](/resources/img/placeholder-60x60.png)
![publication icon](/resources/img/placeholder-60x60.png)
![publication icon](/resources/img/placeholder-60x60.png)
Devito LG
(2023)
Generation of TWO G51D SNCA missense mutation iPSC lines (CRICKi011-A, CRICKi012-A) from two individuals at risk of Parkinson's disease.
in Stem cell research
![publication icon](/resources/img/placeholder-60x60.png)
![publication icon](/resources/img/placeholder-60x60.png)
![publication icon](/resources/img/placeholder-60x60.png)
Saleeb RS
(2023)
Two-color coincidence single-molecule pulldown for the specific detection of disease-associated protein aggregates.
in Science advances
Description | Defining mechanisms in neurons and oligodendrocytes that drive progression in Parkinson's |
Amount | £589,000 (GBP) |
Organisation | Michael J Fox Foundation |
Sector | Charity/Non Profit |
Country | United States |
Start | 02/2023 |
End | 02/2025 |
Description | Understanding the cellular basis of Parkinson's disease dementia |
Amount | £281,071 (GBP) |
Organisation | Parkinson's UK |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 02/2023 |
End | 02/2025 |
Title | A new protocol to derive dopaminergic neurons from iPSCs |
Description | We have worked on developing a method to generate enriched cultures of midbrain neurons that are functionally active, from iPSCs in control and patients with PD causing mutations. This method forms the basis of the platform for all other mechanistic data and therapeutic studies. We will publish this method in due course, but have presented it to internal conferences. |
Type Of Material | Model of mechanisms or symptoms - human |
Year Produced | 2020 |
Provided To Others? | No |
Impact | This method is fast, reliable and much less expensive than current methods used in the literature. Therefore we expect it to have significant impact if adopted. |
Title | Machine Learning and Cellular phenotyping |
Description | I initiated a new collaboration with an AI organisation (Faculty.AI) and my laboratory underwent a training course in python coding, followed by an 8 week fellowship program in training in ML algorithms. We have developed an image analysis pipeline and a disease classifier that can predict disease state in human iPSC derived neurons. |
Type Of Material | Improvements to research infrastructure |
Year Produced | 2021 |
Provided To Others? | No |
Impact | This method is in development, but we expect to publish our first classifier this year. This classifier provides information on disease mechanisms. |
Title | Machine learning classifiers of disease |
Description | We generated a series of classifiers that can predict the chemical subtype of genotype of Parkinson's using images from stem cell derived neurone stained for different intracellular organelles. |
Type Of Material | Computer model/algorithm |
Year Produced | 2023 |
Provided To Others? | Yes |
Impact | -This work is in the top 5% of all research outputs scored by Altmetric. This work was written about by 150 news outlets, including the Daily Mail, The Evening Standard, The Independent (https://www.independent.co.uk/tech/scientists-francis-crick-institute-sonia-gandhi-london-symptoms-b2390970.html), and The National. |
Description | Collaboration with MRC PPU (Alessi group) in Dundee |
Organisation | University of Dundee |
Department | MRC Protein Phosphorylation and Ubiquitylation Unit |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | We established a collaboration with the Alessi group that has enabled proteomic datasets to be generated on our cell models and brain tissue samples |
Collaborator Contribution | Our partners have performed the proteomics analyses and we have provided the sample sets |
Impact | Manuscripts: Protein aggregation and calcium dysregulation are hallmarks of familial Parkinson's disease in midbrain dopaminergic neurons. Virdi GS, Choi ML, Evans JR, Yao Z, Athauda D, Strohbuecker S, Nirujogi RS, Wernick AI, Pelegrina-Hidalgo N, Leighton C, Saleeb RS, Kopach O, Alrashidi H, Melandri D, Perez-Lloret J, Angelova PR, Sylantyev S, Eaton S, Heales S, Rusakov DA, Alessi DR, Kunath T, Horrocks MH, Abramov AY, Patani R, Gandhi S. NPJ Parkinsons Dis. 2022 Nov 24;8(1):162. doi: 10.1038/s41531-022-00423-7. PMID: 36424392 |
Start Year | 2022 |
Description | International Symposium for Movement Disorders |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Supporters |
Results and Impact | I organised a UCL QS Movement Disorders Centre symposium with international and national speakers. This was attended by 200 people face to face, and the audience included all stakeholders - charity, research funders, industry, researchers, and students. |
Year(s) Of Engagement Activity | 2022 |