Mitochondrial and synaptic dysfunction in neurons from patients with OPA1- associated parkinsonism
Lead Research Organisation:
University College London
Department Name: Institute of Neurology
Abstract
The project focuses on identifying and understanding novel mechanisms regulating mitochondrial quality control pathways, which are affected in a variety of neurodegenerative diseases, including Parkinson's Disease and Alzheimer's Disease. In the first part of the project, a high content mitophagy screen will be developed to identify these novel pathways in human neuroblastoma cells. All hits will then be validated and any discovery will be translated in iPSC-derived neurons from Parkinson's Disease patients, to identify any relevant potential therapeutic targets.
Organisations
- University College London (Lead Research Organisation)
- National Institute on Aging (Collaboration)
- UNIVERSITY OF READING (Collaboration)
- Alzheimer's Research UK (Collaboration)
- Institute of Genetics and Molecular and Cellular Biology (IGBMC) (Collaboration)
- Radboud University Nijmegen (Collaboration)
- Medical Research Council (MRC) (Collaboration)
- Cerevance Limited (UK) (Student Project Partner)
Publications
Soutar MPM
(2018)
AKT signalling selectively regulates PINK1 mitophagy in SHSY5Y cells and human iPSC-derived neurons.
in Scientific reports
| Description | EMBL-Wellcome Genome Campus Conference Registration Fee Waiver |
| Amount | € 475 (EUR) |
| Organisation | European Molecular Biology Laboratory |
| Sector | Academic/University |
| Country | Germany |
| Start | 12/2019 |
| End | 12/2019 |
| Description | Exploring the molecular mechanisms of KAT8/KANSL1-dependent regulation of mitophagy |
| Amount | $193,744 (USD) |
| Funding ID | 18651 |
| Organisation | Michael J Fox Foundation |
| Sector | Charity/Non Profit |
| Country | United States |
| Start | 03/2020 |
| End | 09/2021 |
| Title | PINK1 KO SHSY5Y line |
| Description | Used CRISPR/Cas9 to generate a PINK1 knockout line of the Parkin overexpressing cell line we use to screen. We are generating KANSL1 and KAT8 knockout lines at the moment. |
| Type Of Material | Cell line |
| Year Produced | 2019 |
| Provided To Others? | No |
| Impact | This cell line allows to not depend on siRNA to knockdown PINK1, having an easier positive control for all experiments. |
| Title | Mitophagy screen |
| Description | - high content images from mitophagy screen assay development, phosphatome and kinome libraries and GWAS library |
| Type Of Material | Database/Collection of data |
| Year Produced | 2019 |
| Provided To Others? | Yes |
| Impact | -identification of novel hits that may be involved in mitophagy |
| Description | The role of KANSL1 in neurodevelopment and neurodegeneration |
| Organisation | Institute of Genetics and Molecular and Cellular Biology (IGBMC) |
| Country | France |
| Sector | Academic/University |
| PI Contribution | We have identified a novel modulator of mitophagy linked to Parkinson's disease risk, KANSL1. |
| Collaborator Contribution | They have generated and characterised mouse models and iPSC lines from Koolen-de Vries patients, which have KANSL1 haploinsufficiency. |
| Impact | Awarded MJFF funding for 3 years to further explore the contribution of KANSL1 to Parkinson's disease. |
| Start Year | 2019 |
| Description | The role of KANSL1 in neurodevelopment and neurodegeneration |
| Organisation | Radboud University Nijmegen |
| Department | Donders Institute for Brain, Cognition and Behaviour |
| Country | Netherlands |
| Sector | Academic/University |
| PI Contribution | We have identified a novel modulator of mitophagy linked to Parkinson's disease risk, KANSL1. |
| Collaborator Contribution | They have generated and characterised mouse models and iPSC lines from Koolen-de Vries patients, which have KANSL1 haploinsufficiency. |
| Impact | Awarded MJFF funding for 3 years to further explore the contribution of KANSL1 to Parkinson's disease. |
| Start Year | 2019 |
| Description | Understanding Parkinson's Disease GWAS hits |
| Organisation | Alzheimer's Research UK |
| Department | UCL Drug Discovery Institute |
| Country | United Kingdom |
| Sector | Charity/Non Profit |
| PI Contribution | - developing a high content screen for mitophagy - screening the GWAS candidates genes - investigating the biological pathways involved |
| Collaborator Contribution | - investigating the genetic variants identified in the screen |
| Impact | - selected candidate GWAS hits to screen (genetics, bioinformatics) - developed a robust high content siRNA screen for mitophagy (screening) - identified novel genes that might modulate mitophagy (biology) |
| Start Year | 2017 |
| Description | Understanding Parkinson's Disease GWAS hits |
| Organisation | Medical Research Council (MRC) |
| Department | MRC Mitochondrial Biology Unit |
| Country | United Kingdom |
| Sector | Academic/University |
| PI Contribution | - developing a high content screen for mitophagy - screening the GWAS candidates genes - investigating the biological pathways involved |
| Collaborator Contribution | - investigating the genetic variants identified in the screen |
| Impact | - selected candidate GWAS hits to screen (genetics, bioinformatics) - developed a robust high content siRNA screen for mitophagy (screening) - identified novel genes that might modulate mitophagy (biology) |
| Start Year | 2017 |
| Description | Understanding Parkinson's Disease GWAS hits |
| Organisation | National Institute on Aging |
| Department | Laboratory of Neurogenetics |
| Country | United States |
| Sector | Public |
| PI Contribution | - developing a high content screen for mitophagy - screening the GWAS candidates genes - investigating the biological pathways involved |
| Collaborator Contribution | - investigating the genetic variants identified in the screen |
| Impact | - selected candidate GWAS hits to screen (genetics, bioinformatics) - developed a robust high content siRNA screen for mitophagy (screening) - identified novel genes that might modulate mitophagy (biology) |
| Start Year | 2017 |
| Description | Understanding Parkinson's Disease GWAS hits |
| Organisation | University of Reading |
| Department | School of Pharmacy Reading |
| Country | United Kingdom |
| Sector | Academic/University |
| PI Contribution | - developing a high content screen for mitophagy - screening the GWAS candidates genes - investigating the biological pathways involved |
| Collaborator Contribution | - investigating the genetic variants identified in the screen |
| Impact | - selected candidate GWAS hits to screen (genetics, bioinformatics) - developed a robust high content siRNA screen for mitophagy (screening) - identified novel genes that might modulate mitophagy (biology) |
| Start Year | 2017 |
| Description | Parkinson's disease Patient and Public Involvement - Patterns of Perception launch |
| Form Of Engagement Activity | Participation in an activity, workshop or similar |
| Part Of Official Scheme? | No |
| Geographic Reach | Local |
| Primary Audience | Patients, carers and/or patient groups |
| Results and Impact | We were invited to set up a stall on the biology of Parkinson's disease at the launch of the Patterns of Perception movie made by the UCL Movement Disorders centre with Parkinson's patients. We showcased our research and explained what treatment opportunities we are exploring in the lab. |
| Year(s) Of Engagement Activity | 2020 |
| Description | Social Media Public Outreach |
| Form Of Engagement Activity | Engagement focused website, blog or social media channel |
| Part Of Official Scheme? | No |
| Geographic Reach | International |
| Primary Audience | Public/other audiences |
| Results and Impact | We have created Instagram and Twitter channels to show our research and science life to colleagues and the general public, to improve our science communication and network. We have also used it for recruitment purposes and to start a conversation about sustainability in science with other academics and the supplier companies. |
| Year(s) Of Engagement Activity | 2018,2019,2020 |
| URL | https://twitter.com/hpf_lab_ucl?lang=en |