Understanding C9orf72 Hexanucleotide Repeat Linked Toxicity

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.

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.

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.