Understanding C9orf72 Hexanucleotide Repeat Linked Toxicity
Lead Research Organisation:
University College London
Department Name: Genetics Evolution and Environment
Abstract
As humans are living longer than ever before, diseases associated with ageing are becoming increasingly common, in particular neurodegenerative diseases such as dementia, which is currently the leading cause of death in the UK. Neurodegenerative diseases are characterised by a gradual loss of neurons in the brain. Neurons are cells specialised in passing on information, and there are many different types of neurons, each with a specific function. The clinical symptoms of neurodegenerative diseases depend on which type of neuron is dying. For example, in Alzheimer's disease the neurons implicated in memory formation die first, and this is why patients become forgetful and eventually completely lose their memory. In Fronto-temporal dementia (FTD), it is the neurons involved in controlling our personality and so-called executive functions that are lost, and in Amyotropic lateral sclerosis (ALS) it is those controlling movement, so sadly patients end up becoming paralysed. Despite intensive research efforts by scientists around the world, there is currently no cure for any of these neurodegenerative disorders. One of the reasons why it is so difficult to treat these diseases is because we still don't understand why only certain types of neurons die, while others seem unaffected. Why do Alzheimer's patients lose their memory but retain movement, while for ALS patients it is the other way round?
Decades of research revealed that neurodegenerative diseases are caused by the accumulation of certain proteins in the brain. When these proteins malfunction, they can form dense clumps that damage and eventually kill our brain cells as we get older. Each different type of clump triggers death only in specific neurons, but it is unclear why. If we could understand why some neurons can resist being damaged by protein clumps, then we could search for drugs that "help" vulnerable neurons adopt the same protection mechanisms. Or instead we could design drugs to switch off the specific cellular processes that trigger cell death in those neurons.
The aim of this research project is to understand why some neurons die but others survive in neurodegenerative diseases. New cellular mechanisms identified could potentially lead to innovative drug treatments.
We will focus on the most common form of FTD/ALS, which is caused by an alteration (mutation) in a specific gene. We have previously genetically engineered a fruit fly disease model that mimics human FTD/ALS, and we have shown that the neurons in the brains of these flies die, just like in FTD/ALS patients. Compared to more complex models systems, experiments in fruit flies are much quicker and more affordable. And yet about 75% of human disease genes have an equivalent in flies, which means that findings in flies are often directly applicable to the human disease context. For this reason, we will investigate whether the newly discovered cellular mechanisms controlling neuronal death in our fly model also occur in mouse models. These experiments allow us to check whether our findings in flies are also true in a mammalian brain. If these findings hold true in all these model systems, there is a high likelihood the cellular mechanisms discovered in this project will be relevant to patients and therefore provide highly promising therapeutic avenues.
Decades of research revealed that neurodegenerative diseases are caused by the accumulation of certain proteins in the brain. When these proteins malfunction, they can form dense clumps that damage and eventually kill our brain cells as we get older. Each different type of clump triggers death only in specific neurons, but it is unclear why. If we could understand why some neurons can resist being damaged by protein clumps, then we could search for drugs that "help" vulnerable neurons adopt the same protection mechanisms. Or instead we could design drugs to switch off the specific cellular processes that trigger cell death in those neurons.
The aim of this research project is to understand why some neurons die but others survive in neurodegenerative diseases. New cellular mechanisms identified could potentially lead to innovative drug treatments.
We will focus on the most common form of FTD/ALS, which is caused by an alteration (mutation) in a specific gene. We have previously genetically engineered a fruit fly disease model that mimics human FTD/ALS, and we have shown that the neurons in the brains of these flies die, just like in FTD/ALS patients. Compared to more complex models systems, experiments in fruit flies are much quicker and more affordable. And yet about 75% of human disease genes have an equivalent in flies, which means that findings in flies are often directly applicable to the human disease context. For this reason, we will investigate whether the newly discovered cellular mechanisms controlling neuronal death in our fly model also occur in mouse models. These experiments allow us to check whether our findings in flies are also true in a mammalian brain. If these findings hold true in all these model systems, there is a high likelihood the cellular mechanisms discovered in this project will be relevant to patients and therefore provide highly promising therapeutic avenues.
Technical Summary
The increase in average life expectancy has led to a dramatic rise in the number of people globally affected by age-related diseases, in particular neurodegenerative diseases(NDs). Concerted research efforts have successfully identified many of the causative agents of ND. However, the molecular cascades downstream of toxic insults leading to neuronal cell death remain unknown, and there are currently no cures. A major, outstanding question is why cell death is triggered only in specific neuronal populations, while others remain 'protected' or are less susceptible to the accumulation of insults.
To understand how the accumulation of toxic insults triggers cell death in specific neuronal populations, we will focus on C9 toxicity. We have previously developed a fly model of the CCCCGG hexanucleotide repeat expansion(C9), which is the most common cause of sporadic and familial Amyotrophic Lateral Sclerosis(ALS) and Frontotemporal Dementia (FTD). FTD is the second most common early onset dementia, and ALS results in early muscle paralysis and death by respiratory failure within 2-3 years of diagnosis. We have shown in our fly model that C9 repeats are highly toxic to neurons, and large-scale genetic screens and RNA sequencing(RNA-seq) revealed that mitochondrial physiology is a potential modulator of C9 toxicity. Moreover, analyses of depleted transcripts in our C9 fly model have also identified neuronal populations that are vulnerable to C9 toxicity. We propose to further narrow down this identification of neuronal populations vulnerable or resistant to C9 toxicity and then examine their population-specific expression profile, thereby identifying pathogenic and protective cellular responses to toxic insults. This analysis will therefore provide disease relevant new mechanistic insights into the selective vulnerability of neuronal populations to different toxic species and uncover novel candidates for therapeutic development.
To understand how the accumulation of toxic insults triggers cell death in specific neuronal populations, we will focus on C9 toxicity. We have previously developed a fly model of the CCCCGG hexanucleotide repeat expansion(C9), which is the most common cause of sporadic and familial Amyotrophic Lateral Sclerosis(ALS) and Frontotemporal Dementia (FTD). FTD is the second most common early onset dementia, and ALS results in early muscle paralysis and death by respiratory failure within 2-3 years of diagnosis. We have shown in our fly model that C9 repeats are highly toxic to neurons, and large-scale genetic screens and RNA sequencing(RNA-seq) revealed that mitochondrial physiology is a potential modulator of C9 toxicity. Moreover, analyses of depleted transcripts in our C9 fly model have also identified neuronal populations that are vulnerable to C9 toxicity. We propose to further narrow down this identification of neuronal populations vulnerable or resistant to C9 toxicity and then examine their population-specific expression profile, thereby identifying pathogenic and protective cellular responses to toxic insults. This analysis will therefore provide disease relevant new mechanistic insights into the selective vulnerability of neuronal populations to different toxic species and uncover novel candidates for therapeutic development.
Planned Impact
This research will likely have the following impact:
1) Economy
This project will provide employment and high-quality training for two people in one of the world's leading neuroscience research institutions, and thereby contribute to the development of skilled neuroscientists specialised in neurodegeneration research, a rapidly expanding field with significant clinical relevance. Among other invaluable transferable skills, these individuals will gain experience in managing an ambitious multidisciplinary project within a large team and develop oral and written communication skills, including producing and submitting project grants. With their new expertise and research experience, they will be highly employable in academic institutions or the pharmaceutical industry and have great potential for becoming successful independent researchers.
In the long term, this project will provide valuable new insights into long-standing questions and disease processes, and therefore significantly advance the neurodegeneration research field. Importantly, our robust multidisciplinary approach combining two model systems of different complexity, from fruit flies to mice, will allow the identification and validation of potential novel drug targets for ALS and FTD specifically but possibly identify general mechanistic insights for neurodegenerative disease generally. Almost all drugs for these disorders failed at various stages of development and never reached the market, resulting in huge losses for the pharmaceutical industry. The extremely low success rate for neurodegenerative disease drug development is mostly due to our poor understanding of the underlying disease processes. Thus, our project could have a significant impact on the economic performance of the UK pharmaceutical industry by providing the fundamental mechanistic knowledge for developing more effective drug development programs.
2) Patients and their families
Over 20,000 people are living with ALS or FTD in the UK, and more than 850,000 are living with dementia. Caring for these patients has a dramatic impact on the wellbeing of their relatives, who are often primary carers. Despite decades of research, there is still no cure for these diseases. As the research proposed in this project may lead to the development of more effective treatments for neurodegenerative disorders, it could potentially have a highly significant positive impact on the health and wellbeing of patients and their families. In the short term this project will increase our understanding of disease progress, which could help patients deal gain insights into their disease.
3) Healthcare system
The total cost of dementia for the UK government is £26.3 billion. The NHS picks up £4.3 billion of the costs and social care £10.3 billion, which is nearly half of the entire social care budget for adults. Even a partial reduction in the disease burden, and consequently of the care costs, would free valuable resources for the development of other, much needed programs to increase wellbeing and health in our society.
1) Economy
This project will provide employment and high-quality training for two people in one of the world's leading neuroscience research institutions, and thereby contribute to the development of skilled neuroscientists specialised in neurodegeneration research, a rapidly expanding field with significant clinical relevance. Among other invaluable transferable skills, these individuals will gain experience in managing an ambitious multidisciplinary project within a large team and develop oral and written communication skills, including producing and submitting project grants. With their new expertise and research experience, they will be highly employable in academic institutions or the pharmaceutical industry and have great potential for becoming successful independent researchers.
In the long term, this project will provide valuable new insights into long-standing questions and disease processes, and therefore significantly advance the neurodegeneration research field. Importantly, our robust multidisciplinary approach combining two model systems of different complexity, from fruit flies to mice, will allow the identification and validation of potential novel drug targets for ALS and FTD specifically but possibly identify general mechanistic insights for neurodegenerative disease generally. Almost all drugs for these disorders failed at various stages of development and never reached the market, resulting in huge losses for the pharmaceutical industry. The extremely low success rate for neurodegenerative disease drug development is mostly due to our poor understanding of the underlying disease processes. Thus, our project could have a significant impact on the economic performance of the UK pharmaceutical industry by providing the fundamental mechanistic knowledge for developing more effective drug development programs.
2) Patients and their families
Over 20,000 people are living with ALS or FTD in the UK, and more than 850,000 are living with dementia. Caring for these patients has a dramatic impact on the wellbeing of their relatives, who are often primary carers. Despite decades of research, there is still no cure for these diseases. As the research proposed in this project may lead to the development of more effective treatments for neurodegenerative disorders, it could potentially have a highly significant positive impact on the health and wellbeing of patients and their families. In the short term this project will increase our understanding of disease progress, which could help patients deal gain insights into their disease.
3) Healthcare system
The total cost of dementia for the UK government is £26.3 billion. The NHS picks up £4.3 billion of the costs and social care £10.3 billion, which is nearly half of the entire social care budget for adults. Even a partial reduction in the disease burden, and consequently of the care costs, would free valuable resources for the development of other, much needed programs to increase wellbeing and health in our society.
Publications
Xu D
(2023)
A monocarboxylate transporter rescues frontotemporal dementia and Alzheimer's disease models
in PLOS Genetics
Niccoli T
(2021)
Activating transcription factor 4-dependent lactate dehydrogenase activation as a protective response to amyloid beta toxicity.
in Brain communications
Milioto C
(2024)
PolyGR and polyPR knock-in mice reveal a conserved neuroprotective extracellular matrix signature in C9orf72 ALS/FTD neurons.
in Nature neuroscience
Giblin A
(2024)
Neuronal polyunsaturated fatty acids are protective in FTD/ALS
Garrett L
(2022)
Frontotemporal Dementia and Glucose Metabolism
in Frontiers in Neuroscience
Bolukbasi E
(2021)
Cell type-specific modulation of healthspan by Forkhead family transcription factors in the nervous system.
in Proceedings of the National Academy of Sciences of the United States of America
Atilano ML
(2021)
Enhanced insulin signalling ameliorates C9orf72 hexanucleotide repeat expansion toxicity in Drosophila.
in eLife
Anoar S
(2021)
Mitochondria Dysfunction in Frontotemporal Dementia/Amyotrophic Lateral Sclerosis: Lessons From Drosophila Models.
in Frontiers in neuroscience
Description | Alzheimer's Society Studentship |
Amount | £90,762 (GBP) |
Funding ID | 550(AS-PhD-19b-015) |
Organisation | University College London |
Sector | Academic/University |
Country | United Kingdom |
Start | 08/2021 |
End | 09/2024 |
Description | Sponsored Research - 01. Standard Research Project / Programme |
Amount | £13,683 (GBP) |
Organisation | UK Dementia Research Institute |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 03/2021 |
End | 04/2023 |
Description | Wellcome Institutional Strategic Support Fund |
Amount | £19,869 (GBP) |
Organisation | University College London |
Sector | Academic/University |
Country | United Kingdom |
Start | 01/2022 |
End | 08/2022 |
Description | Carrying out single cell sequencing analysis |
Organisation | University College London |
Department | Dementia Research Institute (DRI) |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | We set up, dissected and helped load the single cells sequencing platform. We are now carrying out the bioinformatics analysis |
Collaborator Contribution | Our collaborator trained the post-doc on the project about how to load the single cell sequencing platform, advised and helped with the troubleshooting and is now providing expert input in the analysis of the data. |
Impact | We have generated a large scale single cell sequencing dataset of Drosophila brains expressing C9 repeats. |
Start Year | 2021 |
Description | Confirming candidates from single cell RNAseq in mammalian models |
Organisation | University College London |
Department | Dementia Research Institute (DRI) |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | Using single cell sequencing of a fly model of C9orf72 repeat expansion (the most common mutation leading to ALS and FTD), we identified, in flies, candidate genes that are driving toxicity in neurons and those that are protective to disease. |
Collaborator Contribution | Our partners are in the process of checking in iPSC models and mouse brains whether genes that we think are relevant to disease are upregulated or downregulated. |
Impact | No outputs to report yet. |
Start Year | 2021 |
Description | Confirming candidates from single cell RNAseq in mammalian models |
Organisation | University College London |
Department | Dementia Research Institute (DRI) |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | Using single cell sequencing of a fly model of C9orf72 repeat expansion (the most common mutation leading to ALS and FTD), we identified, in flies, candidate genes that are driving toxicity in neurons and those that are protective to disease. |
Collaborator Contribution | Our partners are in the process of checking in iPSC models and mouse brains whether genes that we think are relevant to disease are upregulated or downregulated. |
Impact | No outputs to report yet. |
Start Year | 2021 |
Description | London Academy of Excellence Tottenham UCL visit |
Form Of Engagement Activity | Participation in an open day or visit at my research institution |
Part Of Official Scheme? | No |
Geographic Reach | Local |
Primary Audience | Schools |
Results and Impact | 90 6th form students from a UCL target school for widening participation visited our department. The school reported a 30% increase in applications to Biosciences degrees at Univeristy. And a 15% increase to applications to UCL. |
Year(s) Of Engagement Activity | 2022 |
Description | Panelist for a webinar entitled "Returning to a STEMM career after a caregiving break" |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Other audiences |
Results and Impact | I was part of a panel of 4 mothers working in sciences and funders, sharing our experiences and opportunities for mothers returning to science after a career break and answering questions from the audience. The audience reported finding the discussion really useful. The panel discussion was summarised in a website, and is now accessible to other mothers needing advice. |
Year(s) Of Engagement Activity | 2022 |
URL | https://www.mothersinscience.com/scimomchats/returning-stemm-career-after-caregiving-break |
Description | Talk to clients of Age UK centre |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | Local |
Primary Audience | Public/other audiences |
Results and Impact | Presented the work of the laboratory and the Institution to a group of regular clients of an Age UK cafe morning |
Year(s) Of Engagement Activity | 2022 |