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.
 
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