Investigating Novel Stress Response Pathways in Neurological Disease

Lead Research Organisation: MRC Mammalian Genetics Unit

Abstract

Neurodegenerative disease is becoming an increasing burden on healthcare and there is a continuing need to understand the cellular mechanisms involved and generate new therapeutic approaches. One important question to address is why distinct populations of cells in the brain are vulnerable in these disorders.
Oxygen is vital for life, but certain oxygen species can cause damage to cells if their levels are not properly controlled. In cells in the brain this is particularly important, and it has been shown that a build-up of these reactive oxygen species, also known as oxidative stress, is a key feature of localised cell death in neurodegenerative disease. Therefore, identification of pathways that counteract this oxidative damage may identify new therapeutic strategies that are widely applicable to human disease.

This research programme focusses on investigating the function of a family of proteins that we have shown can be protective against oxidative stress. Importantly, one of these proteins called TBC1D24, when mutated, causes a range of serious neurological disorders. We will use a combination of experiments in cells and also in mouse models to study these proteins. We hope our work will help TBC1D24 patients in the future, but also to understand more about how cells in the brain respond to oxidative stress, a fundamental biological process.

Technical Summary

Oxidative stress (OS) is a hallmark of major neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS), Parkinson’s and Alzheimer’s disease as well as ageing. Importantly, OS markers are present in cell populations selectively targeted in neurodegeneration, and pathogenic mutations occur in proteins that feature prominently in antioxidant pathways. OS is also an important feature of many other major neurological disorders including multiple sclerosis and epilepsy. This project, focussing on a particular protein family, is to determine how aberrant OS defence pathways lead to neuronal damage, and ultimately whether therapeutic up-regulation of antioxidants could be applied across neurodegenerative / neurological disorders.

This 3-year Programme builds on data we have generated, demonstrating that a family of proteins, that includes oxidation resistance 1 (OXR1), is a critical component of the OS response in neurons. We have gone on to show that deletion of Oxr1 causes cell-specific neurodegeneration in mice, while the protein itself is also an early marker for cell death in the CNS. Furthermore, in investigating a specific neurodegenerative disease as a proof of principle, we now know that Oxr1 and related proteins can protect against OS when over-expressed in both cellular and mouse models of ALS. Significantly, one of these OXR1-related proteins, TBC1D24, has been discovered recently to be mutated in multiple inherited forms of epilepsy that are also characterised by neurodegeneration; nevertheless, how these mutations cause this range of serious neurological disorders is unknown.

The aim of this Programme is to understand the function of OXR1-related proteins in the OS response and in neurological disease. The project will harness the power of mouse genetics at the Mammalian Genetics Unit (MGU) in combination with our specific expertise in studying the molecular mechanisms of neuronal function and degeneration. We are taking a systematic approach to understand the function of TLDc proteins, examining their potentially unique and overlapping roles in neuronal cells, in addition to determining how human mutations influence key aspects of these functions. Furthermore, we hope to determine whether phenotype-genotype correlations can be identified to assist future clinical outcomes in patients.

Publications

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Castroflorio E (2020) The Ncoa7 locus regulates V-ATPase formation and function, neurodevelopment and behaviour in Cellular and Molecular Life Sciences

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Finelli MJ (2017) TLDc proteins: new players in the oxidative stress response and neurological disease. in Mammalian genome : official journal of the International Mammalian Genome Society

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Merkulova M (2018) Targeted deletion of the Ncoa7 gene results in incomplete distal renal tubular acidosis in mice. in American journal of physiology. Renal physiology

 
Description Modulating the communication within brain cells by the epilepsy gene TBC1D24
Amount £20,000 (GBP)
Organisation Epilepsy Research UK 
Sector Charity/Non Profit
Country United Kingdom
Start 12/2018 
End 06/2020
 
Description Investigating the protective role of OXR1 in models of Alzheimer's disease 
Organisation Buck Institute for Age Research
Country United States 
Sector Charity/Non Profit 
PI Contribution Supplying mouse models of OXR1 over-expression
Collaborator Contribution Supplying novel models of AD
Impact N/A
Start Year 2019
 
Description Protective role of OXR1 in Parlinson's disease 
Organisation Medical University of South Carolina
Country United States 
Sector Academic/University 
PI Contribution Investigating the role of OXR1 as a protective factor in rodent models of PD - supplying mice
Collaborator Contribution Investigating the role of OXR1 as a protective factor in rodent models of PD - supplying mice PD models and data analysis
Impact Poster at SFN 2019
Start Year 2018
 
Description Role of TLDc proteins in lysosomal function 
Organisation University of Oxford
Country United Kingdom 
Sector Academic/University 
PI Contribution Providing novel genetic tools
Collaborator Contribution Providing expertise in lysosomal biology
Impact ERUK Pilot Grant funding
Start Year 2018
 
Description Role of TLDc proteins in viral infection 
Organisation Francis Crick Institute
Country United Kingdom 
Sector Academic/University 
PI Contribution Supplying tissue samples for in vitro cellular assays at The Crick
Collaborator Contribution Assayaing viral infection in vitro
Impact Preliminary in vitro studies
Start Year 2019
 
Description Role of TLDc proteins in viral infection 
Organisation King's College London
Country United Kingdom 
Sector Academic/University 
PI Contribution Supplying tissue samples for in vitro cellular assays at The Crick
Collaborator Contribution Assayaing viral infection in vitro
Impact Preliminary in vitro studies
Start Year 2019
 
Description Synaptic function of TLDc proteins 
Organisation University of Genoa
Country Italy 
Sector Academic/University 
PI Contribution Providing new genetic (mouse) tools
Collaborator Contribution Provided data on synaptic physiology and structure in mouse models
Impact Manuscript is in preparation for submission in 2018
Start Year 2017
 
Description International League Against Epilepsy - meet the scientist session 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact Brief presentation explaining new ERUK funding to public attendees to ILAR meeting in Birmingham followed by meet-and-greet session for
questions
Year(s) Of Engagement Activity 2019
 
Description University of the third age (U3A) site visit 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact MRC Harwell site visit by 20 U3A members including a set of talks on experimental work in the Unit, including one on neurological disease research
Year(s) Of Engagement Activity 2018