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Dr Adrian Isaacs
UCL Institute of Neurology
Queen Square
London
WC1N 3BG
Appointment
  • Reader in Neurodegenerative Disease
  • Neurodegenerative Diseases
  • Institute of Neurology
  • Faculty of Brain Sciences
Research Groups
Research Themes
Research Summary
   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 cells 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. This is particularly important as lysosomal degradation is also impaired by other neurodegenerative disease genes such as PSEN1, VCP and FIG4. To address this question we developed the first mouse model of FTD caused by CHMP2B mutation. We are investigating primary cortical neurons and brain tissue from these mice using a range of imaging and proteomic approaches. We are also developing throughput cellular screens in collaboration with the MRC Laboratory for Molecular Cell Biology, in order to identify genes and small molecules that can modulate these pathways.
  
An expanded GGGGCC repeat in a non-coding region of C9orf72 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. We are investigating both RNA and RAN protein mechanisms in cell culture and animal models. We have also shown, using biophysical methods, that the GGGGCC repeat RNA forms a structure termed a G-quadruplex. We are currently collaborating with the UCL School of Pharmacy to screen G-quadruplex-binding small molecules to determine their therapeutic potential.
Teaching Summary

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.

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