DrCarol Dobson-Stone

Project Opportunities

Title: The role of a novel mutant gene in dementia and motor neuron disease

Summary of opportunity:

We have identified a new gene that when mutated causes dementia and motor neuron disease (MND), diseases that are currently incurable. This project will examine how this mutated gene affects cell functions to cause nerve cell death, and find out whether people who have more common variants of this gene are at greater risk of developing dementia or MND. This knowledge is crucial for diagnosing and developing therapies for these disorders.

Opportunity synopsis:

Frontotemporal dementia (FTD), a common cause of early-onset dementia, is characterised by behavioural and/orspeech changes followed by progressive cognitive deficits arising from degeneration of nerve cells (neurons). FTD shows significant clinical and pathological overlap with motor neuron disease (MND), a rapidly progressive neurodegenerative disorder. There are no effective cures for FTD or MND. Our understanding of FTD and MND has been greatly enhanced by identifying the genes and pathways that underlie the neurodegenerative process. We have identified a new disease gene encoding an enzyme involved in autophagy, one of the processes by which unwanted and/or misfolded proteins are removed by the cell.

The aims of this project are to assess the impact of this mutant gene on autophagy and other cellular pathways, using molecular biology and cell culture techniques, and to determine whether rare and common DNA variants of this gene are associated with cognitive performance and disease risk in elderly individuals. Understanding the biological pathways that lead from mutated gene to neuron death and identifying DNA variants that increase disease risk or specific cognitive deficits is important for improving disease diagnosis and identifying new targets for development of a treatment for these disorders.

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Project Opportunities

Title: Role of the CYLD gene in dementia and motor neuron disease

Summary of opportunity:

We have identified a gene, CYLD, that when mutated causes dementia and motor neuron disease (MND), diseases that are currently incurable. This project will investigate the effects of CYLD mutations on cell survival and examine how CYLD interacts with proteins known to be involved in FTD and ALS. By understanding how CYLD interacts with other proteins in the body, this project will identify new targets for developing treatments.

Opportunity synopsis:

Frontotemporal dementia (FTD), a common cause of early-onset dementia, is characterised by behavioural and/or speech changes followed by progressive cognitive deficits arising from degeneration of nerve cells (neurons). FTD shows significant clinical and pathological overlap with motor neuron disease (MND), a rapidly progressive neurodegenerative disorder. There are no effective cures for FTD or MND. Our understanding of FTD and MND has been greatly enhanced by identifying the genes and pathways that underlie the neurodegenerative process. We recently identified a new genetic cause of FTD and MND: a mutation in CYLD.

Using molecular biological and cell culture techniques, the aims of this project are: to determine whether other CYLD gene variants identified in FTD, MND and Alzheimer’s disease patients are pathogenic; to examine CYLD binding to and processing of other known FTD and MND genes; and to identify CYLD targets affecting nerve cell survival. Understanding the biological pathways that lead from CYLD mutation to cell death will help uncover the underlying pathogenic mechanism and help understand how these could be targeted as a treatment for these disorders.

----------Current Research Projects----------

1. Developing a bioinformatics pipeline to screen through next-generation sequencing data from ~400 dementia patients to identify potentially pathogenic DNA variants in highly plausible candidate genes.
2. Designing high-throughput cellular assays of dementia-relevant biological phenotypes for screening DNA variants, to determine which variants have a functional effect and therefore may cause disease.
3. Characterisation of a novel FTD-MND gene. We are examining how this mutated gene affects cell functions to cause nerve cell death, using cutting-edge cell and mouse models of disease, and examining whether people who have certain common variants of this gene are at greater risk of developing dementia or MND.