Project 1 - Glucose Metabolism in Dementia
in collaboration with Adrian Isaacs Laboratory UK DRI
Our brains consume 20% of our body's energy. However, nerve cells can't store energy or use fat as a fuel so they have to generate all their energy from sugar. The brain has complex molecular mechanisms to ensure a constant supply of sugar to nerve cells, but in people with dementia this system breaks down as disease progresses.
We recently discovered that improving sugar delivery helps nerve cells cope with the effects of toxic proteins associated with Alzheimer's Disease. We are now extending this work to another type of dementia: Frontotemporal Dementia (FTD), the second most common early-onset dementia. We use a fly model expressing the most common mutation linked to FTD, a hexanucleotide repeat expansion in the human gene C9orf72 (C9). We are investigating glucose metabolism in this model and investigating whether modulating glucose metabolism can affect C9 toxicity. We will confirm the discoveries from flies in mouse models and in cells donated by FTD patients.
Project 2 - Down Syndrome's and Alzheimer's Disease
in collaboration with Frances Wiseman Laboratory UCL IoN
People with Down Syndrome (DS) are at greater risk of developing early onset Alzheimer's Disease (AD) than the general population. DS is caused by an extra copy of human chromosome 21 (Hsa21), which encodes 234 genes. One of these genes, APP, codes for a protein that is cleaved to form the amyloid plaque (Aβ) that accumulates in the brain in the early stages of AD. How the other genes on Hsa21 affect disease is not yet understood;. Frances Wiseman has recently shown using mouse model that a stretch of 39 Hsa21 orthologues can exacerbate Aβ deposition in the brain. We will now use fly models to pinpoint which of these genes is responsible for this effect. We will go on to investigate the role of this gene in disease, in collaboration with human clinical and genetic data sets collected by LonDownS consortium. This approach will replace the use of mouse Aβ aggregation models to investigates this questions, thus significantly reducing use of animals.
Project 3: Cell death in neurodegeneration
in collaboration with Adrian Isaacs Laboratory and Carlo Sala Frigerio Laboratory, UK DRI
Neurodegenerative diseases are characterised by a gradual loss of neurons in the brain and concerted research efforts have successfully identified many of the causative agents of neurodegenerative diseases. 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. Why do Alzheimer's patients lose their memory but retain movement, while for ALS patients it is the other way round?
The aim of this research project is to understand why some neurons die but others survive in neurodegenerative diseases. We will focus on the most common form of FTD/ALS, which is caused by a hexanucleotide repeat expansion in the human gene C9orf72 (C9). We are in the process of identifying 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.
Project 4: Mitochondria in Amyotrophic Lateral Sclerosis and Frontotemporal Dementia
In collaboration with Nick Lane Laboratory UCL GEE
Mitochondria are the power house of every cell, creating energy to fuel each cell’s function. They have been involved in a multitude of neurodgenerative disease and have been implicated in dementia and movement disorders. We are investigating the potential role of mitochondrial physiology in the development of disease associated with the hexanucleotide repeat expansion in the human gene C9orf72 (C9), the most common genetic cause of FTD/ALS (Frontotemporal Dementia/Amyotrophic Lateral Sclerosis).