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C9orf72-mediated neurodegeneration: mechanisms and therapeutics

Periodic Reporting for period 3 - C9ND (C9orf72-mediated neurodegeneration: mechanisms and therapeutics)

Reporting period: 2018-10-01 to 2020-03-31

Frontotemporal dementia and amyotrophic lateral sclerosis are devastating neurodegenerative diseases which have no effective therapies. Frontotemporal dementia can cause changes in a person’s personality, behaviour or language abilities. Amyotrophic lateral sclerosis causes muscle weakness, which rapidly leads to paralysis and death. Some people can develop both frontotemporal dementia and amyotrophic lateral sclerosis, which indicates that the two diseases can be caused by the same factors. The most common cause of both diseases is a mutation in the C9orf72 gene. The mutation comprises of a small section of DNA within the C9orf72 gene that becomes repeated hundreds to thousands of times. This type of mutation is termed a repeat expansion. We have previously shown that these repeats are very harmful to neurons. This project aims to better understand how the C9orf72 repeats causes neurons to die and to identify new genes that can protect against their harmful effects. In addition we plan to investigate new compounds that can target the C9orf72 repeats and assess their potential as therapeutics.

We will do this using a range of different model systems. We will use fruit flies as they have been very successful in identifying the causes of other neurodegenerative diseases. They also have unparalleled genetic tools for investigating both normal physiology and disease. We will also analyse neurons we have derived from people with the C9orf72 repeat mistake. This is also a powerful system as it will ensure that our findings are relevant to human patients. This combined approach has the potential to deliver fundamental new insight into the causes of frontotemporal dementia and amyotrophic lateral sclerosis.
We previously engineered fruit flies to contain the C9orf72 repeat expansion. We have now analysed over 2000 genes to assess which ones can protect against the harmful effects of the C9orf72 repeat expansion. We have identified 16 genes that can alleviate the neurodegeneration caused by the C9orf72 repeats. It was only possible to test so many genes by using a genetically tractable model organism like fruit flies. None of these genes have so far been shown to have a role in C9orf72 disease. Therefore these new genes are a very exciting step forward in our understanding of the disease. They also raise the potential of finding new ways to prevent it.

In addition we have also identified new compounds that can bind to the C9orf72 repeats. We have shown that these compounds reduce the toxic properties of the repeats in both fruit flies and neurons derived from people with the C9orf72 repeat expansion. This provides proof of concept for further development of drugs using this approach.
We have identified 16 genes that can alleviate the harmful effects of the C9orf72 repeat expansion in fruit flies. None of these genes have been implicated previously in C9orf72 disease. Therefore this marks a very clear progression beyond the current state of the art.
Human neuronal cultures