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- Reader in Neurodegenerative Disease
- Neurodegenerative Diseases
- Institute of Neurology
- Faculty of Brain Sciences
My group studies the molecular basis of two related neurodegenerative diseases: frontotemporal dementia (FTD) and motor neuron disease (MND). FTD is a common form of young-onset dementia and is characterised by changes in personality and language. MND is characterised by progressive weakness and paralysis. FTD and MND can be caused by mutations in the same gene, and can co-occur in the same individual. Therefore, FTD and MND are now considered overlapping clinical syndromes with common causes.
Our approach is to generate cellular and animal models of genetically inherited forms of FTD and MND, in parallel with analysis of patient iPSC-neurons and brain tissue, in order to elucidate the mechanisms that lead to neuronal dysfunction and death. We are also developing drug screens based on this knowledge to identify potential therapeutics. Our main focus is on two disease genes, CHMP2B and C9orf72.
CHMP2B causes frontotemporal dementia linked to chromosome 3, a rare form of FTD that occurs in a large Danish family. CHMP2B is part of ESCRT-III (endosomal sorting complex required for transport-III), a multi-protein complex required for degradation events in the autophagy and endosome-lysosome pathways. We have shown that mutant CHMPB affects degradation in both of these pathways and are interested in how defects in these essential lysosomal degradation pathways specifically lead to impaired neuronal function. To address this question we are using a range of imaging and proteomic approaches in our collection of models and patient tissue. We are also testing therapeutic approaches that can alleviate endo-lysosome dysfunction in these models.
An expanded GGGGCC repeat in a non-coding region of the C9orf72 gene is the most common known cause of both FTD and MND. We have shown that the expanded repeats form nuclear RNA aggregates in patient brain, which may cause toxicity by sequestering RNA-binding proteins. Remarkably, the expanded repeats can initiate their own translation via a phenomenon termed repeat associated non-ATG (RAN) translation. RAN proteins also aggregate in patient brain and we have shown that they can be potently neurotoxic in vivo. We are currently investigating both RNA and RAN protein mechanisms of neurodegeneration using a range of model systems including Drosophila and patient iPSC-neurons.We have also shown, using biophysical methods, that the GGGGCC repeat RNA forms a structure termed a G-quadruplex. We are now collaborating with the UCL School of Pharmacy to develop G-quadruplex-binding small molecules as potential therapeutics.
I am a tutor and lecturer for the MSc in Clinical Neuroscience based at the UCL Institute of Neurology and also a co-convenor for the Cellular and Molecular Mechanisms of Disease module.