Understanding the role of neurodegenerative disease risk genes in the ageing nervous system
Lead Research Organisation:
CARDIFF UNIVERSITY
Department Name: UNLISTED
Abstract
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Technical Summary
Though many common neurodegenerative diseases exist in hereditary forms, the vast majority of cases occur sporadically. Human genetic studies have identified many genetic loci and polymorphisms associated with increased risk of developing disorders such as Alzheimer’s disease, however it is frequently unclear how these mutations contribute to pathogenesis. Furthermore it is often the case that the relevant cell type and/or effect upon gene expression accompanying a given genetic association are unclear. Using a combined approach of invertebrate genetics and mammalian cellular model systems we aim to understand how genes associated with increased risk for neurodegenerative diseases contribute to maintenance of the ageing nervous system, focusing on genes linked to sporadic, late-onset Alzheimer’s disease. Using the fruitfly Drosophila melanogaster and powerful invertebrate screening techniques, we aim to understand the effect of cell types specific, altered expression of AD associated genes upon age associated phenotypes, including behaviour, lifespan, neuronal activity, neurodegeneration and autophagosome-lysosome biology. Where appropriate, altered phenotypes and cellular mechanisms identified in our Drosophila screens will be validated in mammalian cell culture system, aiming to identify candidate genes and cellular mechanism for therapeutic intervention.
In addition to our studies of late-onset AD risk genes, we are also utilizing a high-content image analysis approach to understand the contribution of stress on cellular models of amyotrophic lateral sclerosis/frontotemporal dementia. Though ALS and FTD manifest as distinct conditions driven by neurodegeneration in differing regions of the brain, emerging genetic data suggests these disorders exist on a genetic spectrum, with several genes such as C9ORF72 and TBK1 identified in pedigrees where both disorders occur either separately or in combination. The source of this phenotypic heterogeneity within these families is unclear, however is suggestive of genetic or environmental factors modifying pathogenesis. Through use of high-content image analysis we are assessing how different forms of stress (immune, redox, metabolic, etc) induce distinct cellular responses in challenged neurons, and how these are altered by manipulation of genes associated with ALS/FTD. Ultimately we aim to understand how interaction between genetic and environmental factors drive the pathogenesis in these disorders and determine if specific forms of stress result in distinct cellular phenotypes associated with ALS and/or FTD.
In addition to our studies of late-onset AD risk genes, we are also utilizing a high-content image analysis approach to understand the contribution of stress on cellular models of amyotrophic lateral sclerosis/frontotemporal dementia. Though ALS and FTD manifest as distinct conditions driven by neurodegeneration in differing regions of the brain, emerging genetic data suggests these disorders exist on a genetic spectrum, with several genes such as C9ORF72 and TBK1 identified in pedigrees where both disorders occur either separately or in combination. The source of this phenotypic heterogeneity within these families is unclear, however is suggestive of genetic or environmental factors modifying pathogenesis. Through use of high-content image analysis we are assessing how different forms of stress (immune, redox, metabolic, etc) induce distinct cellular responses in challenged neurons, and how these are altered by manipulation of genes associated with ALS/FTD. Ultimately we aim to understand how interaction between genetic and environmental factors drive the pathogenesis in these disorders and determine if specific forms of stress result in distinct cellular phenotypes associated with ALS and/or FTD.
Publications
Aubrey LD
(2024)
Substitution of Met-38 to Ile in ?-synuclein found in two patients with amyotrophic lateral sclerosis induces aggregation into amyloid.
in Proceedings of the National Academy of Sciences of the United States of America
Kahriman A
(2023)
Repeated mild traumatic brain injury triggers pathology in asymptomatic C9ORF72 transgenic mice.
in Brain : a journal of neurology
Maddison DC
(2023)
COPI-regulated mitochondria-ER contact site formation maintains axonal integrity.
in Cell reports
Malik BR
(2019)
Autophagic and endo-lysosomal dysfunction in neurodegenerative disease.
in Molecular brain
Peters OM
(2021)
A nod and a Wnk to axon branching and destruction.
in Neuron
Townsend LN
(2023)
Cdk12 maintains the integrity of adult axons by suppressing actin remodeling.
in Cell death discovery
Related Projects
Project Reference | Relationship | Related To | Start | End | Award Value |
---|---|---|---|---|---|
MC_PC_16030 | 01/02/2017 | 30/11/2021 | £970,468 | ||
MC_PC_16030/2 | Transfer | MC_PC_16030 | 31/03/2017 | 30/11/2021 | £485,234 |
MC_PC_16030/1 | 01/11/2018 | 30/11/2021 | £485,234 | ||
MC_PC_16030/2 | Transfer | MC_PC_16030/1 | 31/03/2017 | 30/11/2021 | £485,234 |
Description | ARUK Small Project Grant |
Amount | £5,000 (GBP) |
Organisation | Alzheimer's Research UK |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 12/2018 |
End | 06/2019 |
Description | Functional characterisation of newly identified Alzheimer's Disease associated genes in human and invertebrate model systems |
Amount | £637,641 (GBP) |
Funding ID | MR/W004879/1 |
Organisation | Medical Research Council (MRC) |
Sector | Public |
Country | United Kingdom |
Start | 11/2021 |
End | 10/2024 |
Description | Match funding Cardiff University Neuroscience and Mental Health Institute / UK Dementia Research Institute studentship (funding reported for consumables only - student fees and stipend also awarded through this scheme) |
Amount | £30,000 (GBP) |
Organisation | Cardiff University |
Sector | Academic/University |
Country | United Kingdom |
Start | 09/2018 |
End | 09/2021 |
Description | PhD Studentship - Cardiff University, School of Biosiences: 40% supervision (consumable only reported; stipend and fees are also supported by Cardiff University) |
Amount | £10,500 (GBP) |
Organisation | Cardiff University |
Sector | Academic/University |
Country | United Kingdom |
Start | 09/2018 |
End | 09/2021 |
Description | Recruitment of MRes student through Cardiff University School of Biosciences research programme |
Amount | £2,000 (GBP) |
Organisation | Cardiff University |
Sector | Academic/University |
Country | United Kingdom |
Start | 02/2018 |
End | 07/2018 |
Description | Ser Cymru Enhancing Competitiveness Infrastructure Award |
Amount | £5,000 (GBP) |
Organisation | Government of Wales |
Sector | Public |
Country | United Kingdom |
Start | 03/2020 |
End | 03/2020 |
Description | Wellcome Trust Neuroscience PhD studentship |
Amount | £130,000 (GBP) |
Funding ID | 222307/Z/21/Z |
Organisation | Wellcome Trust |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 07/2020 |
End | 09/2023 |
Description | ARUK Small Project Grant |
Organisation | University of Bristol |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | Collaboration to assay Drosophila models of Alzheimer's disease risk genes identified through epigenome wide association study, working with Dr James Hodge, University of Bristol and Dr Gaynor Smith (Cardiff University, UKDRI). |
Collaborator Contribution | James Hodge will be conducting learning behavioural analysis of transgenic drosophila Gaynor Smith will be conducting histological and biochemical analysis of transgenic drosophila |
Impact | £5000 funding split between three research groups - reported in funding |
Start Year | 2018 |
Description | Collaboration with PerkinElmer to conduct high content image analysis |
Organisation | PerkinElmer |
Country | United States |
Sector | Private |
PI Contribution | PhD studentship to conduct high content image analysis of gene linked to ALS/FTD neurodegeneration. |
Collaborator Contribution | PerkinElmer have give no-cost access to a field specialist (daily rate = £1850) and TIBCO Spotfire Data Visualisation Software (value £6396). |
Impact | PhD studentship funding provided through NMHRI and UKDRI at Cardiff University - reported in Funding section. |
Start Year | 2018 |
Description | Proteomic collaboration with University of Dundee |
Organisation | University of Dundee |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | Pharmacological inhibition of TBK1 in immortalized neuroblastoma and microglial cells; preparation of samples |
Collaborator Contribution | Collaboration with Prof Dario Alessi to determine role of TBK1 in regulating neuronal and glial proteome. Alessi lab conducted quantitative TMT LC-MS analysis of neuroblastoma/microglia pharmacologically inhibted for TBK1 activity, and statistical analysis of proteomic data. |
Impact | Data has been included in presentations assocaited with the MRC Momenum project, and will contribute towards future research publications. Data from these cell lines has also been included in an online proteomics resource being developed by University of Dundee (http://copica.proteo.info/#/home). |
Start Year | 2021 |
Description | Alzheimer's Society Cymru |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Supporters |
Results and Impact | Alzheimer's Society Cymru conference. Role: invited speaker to diseminate research from UKDRI at Cardiff University. |
Year(s) Of Engagement Activity | 2019 |
URL | https://twitter.com/SianBlackham/status/1103656067119177728 |
Description | Brain Games |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Public/other audiences |
Results and Impact | Brain Games Was an open day at Cardiff Museum, members of the public (largely children) came to learn about Neuroscience through interactive "drop-in" stations, consisting of mind puzzles, arts and crafts and other activities. |
Year(s) Of Engagement Activity | 2018,2019 |
URL | https://museum.wales/cardiff/whatson/10492/Brain-Games/ |
Description | Glial role of small wing/PLCG2 in modifying amyloid associated phenotypes in Drosophila (oral presentation by PhD student assocaited with project) |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Postgraduate students |
Results and Impact | Glia in Neuroinflammation UK DRI ECR event, London (2021). PhD student attended glia workshop supported by the UK DRI, receiving questions from audience and feedback from experts working within the field of inflammation. |
Year(s) Of Engagement Activity | 2021 |
Description | Investigating Roles of Alzheimer's Disease Risk Genes in Glia Throughout Age, Using Drosophila (oral presentation) |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Postgraduate students |
Results and Impact | ARUK conference 2021 ECR day, Virtual (2021). Online conference for ECRs working within Alzheimer's disease field. Student gave an oral presentation of work assocaited with the project, receiving questions and discussion from the audience. |
Year(s) Of Engagement Activity | 2021 |
Description | Investigating Roles of Alzheimer's Disease Risk Genes in Glia Throughout Age, Using Drosophila (poster presentation) |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Postgraduate students |
Results and Impact | Neurofly 2020, Virtual (2021). PhD student attended online conference to present and discuss work assocaited with the project. Received questions and discussion from the audience. |
Year(s) Of Engagement Activity | 2021 |
Description | Pint of Science |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | Local |
Primary Audience | Public/other audiences |
Results and Impact | Discussion of uses of Drosophila in neuroscience and dementia research to lay audience. |
Year(s) Of Engagement Activity | 2019 |
URL | https://pintofscience.co.uk/city/cardiff |
Description | Royal Society of Biology, Dementia Panel: Cardiff University |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Public/other audiences |
Results and Impact | Presentation of Alzheimer's disease genetics and Peters lab research, followed by panel discussion, to local members of Royal Society of Biology. |
Year(s) Of Engagement Activity | 2019 |
Description | STEM abassador training |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | Local |
Primary Audience | Other audiences |
Results and Impact | Training in local STEM Ambassador Hub (Cardiff) to gain recognition as local STEM ambassador. Planning to attend Brain Games event in Cardiff Museum March 19th 2018 to engage with local lay population. |
Year(s) Of Engagement Activity | 2018 |
Description | TBK1: Another reason to stress about FTD/ALS? (poster delivered by PhD student) |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Postgraduate students |
Results and Impact | CytoData 2019, Heidelberg, Germany. PhD student assocaited with the grant attended a bioinformatics conference focused, presented imaging informatic component of their project and received comments and discussion from audience. |
Year(s) Of Engagement Activity | 2019 |
Description | UCL IHA Virtual Symposium: Neurodegeneration in Flies |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Postgraduate students |
Results and Impact | Online symposium presentation to discuss research from this project with the international drosophila neurodegenerative disease community. |
Year(s) Of Engagement Activity | 2021 |
URL | https://www.ucl.ac.uk/biosciences/departments/genetics-evolution-and-environment/research/institute-... |
Description | Understanding Alzheimer's Disease Risk Gene Functions, Using Drosophila Models (poster presented by PhD students assocaited with grant). |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Postgraduate students |
Results and Impact | 3rd Molecular Biology and Ageing conference, Groningen. PhD student received questions and discussion from audience members |
Year(s) Of Engagement Activity | 2019 |
Description | Understanding Alzheimer's Disease Risk Gene Functions, Using Drosophila Models (poster) |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Postgraduate students |
Results and Impact | 12th UK Korea Neuroscience symposium, London. Research conference for UK and Korean researchers working across neuroscience |
Year(s) Of Engagement Activity | 2019 |
Description | Understanding Roles of Alzheimer's Risk Genes on Ageing Glia Biology, Using the Power of Drosophila Melanogaster (online poster delivered by student associated with grant) |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Postgraduate students |
Results and Impact | Alzheimer's Association International Conference: Neuroscience Next, Virtual (2021). PhD student attended virtual meeting to present work assocaited with the grant. Had discussion and questions from audience members about research. |
Year(s) Of Engagement Activity | 2021 |
Description | Understanding Roles of Alzheimer's Risk Genes on Ageing Glia Biology, Using the Power of Drosophila Melanogaster (online poster delivered by student associated with grant) |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Postgraduate students |
Results and Impact | AD-PD 2021, Virtual conference. Student delivered poster, recieving questions and discussion from online audience. |
Year(s) Of Engagement Activity | 2021 |
Description | Understanding the role of ALS/FTD gene TBK1 in cellular response to stress (poster delivered by OP). |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Postgraduate students |
Results and Impact | Japan-UK Neuroscience Symposium, Chiba, Japan; Internartional meeting bringing together UK and Japanese researchers to discuss advances in neuroscience. Poster generated discussion and interaction with group leaders and graduate students. |
Year(s) Of Engagement Activity | 2019 |