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Project 1 - Pyruvate Metabolism in Dementia

in collaboration with Adrian Isaacs Laboratory UK DRI , Selina Wray Laboratory, IoN, UCL and Dr Sophie Trefely, Babraham Institute

 

Dementias are caused by the accumulation of toxic proteins in the brain of patients. Different types of dementias are caused by different types of proteins, however when patients go to the clinic, it's often quite difficult to say which type of dementia the patient is presenting with. A therapeutic approach valid across different dementias would therefore be very useful, as it would not be reliant on accurate diagnosis.

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We use fly models of both Frontotemporal Dementia (FTD) and Alzheimer’s disease (AD). Our FTD model expresses the most common mutation linked to FTD, a hexanucleotide repeat expansion in the human gene C9orf72 (C9), whereas we model whereas our AD model expresses Aß1-42 peptide, a major hallmark of disease. Using these models, we recently discovered that increasing the amount of pyruvate in brain cells led to a drop in the levels of a number of toxic proteins, associated both with FTD and AD. We also found that decreasing these proteins led to an improvement of the lifespan and behaviour of fly models of disease.

 

This project will look into the details of how the increase in pyruvate leads to the breakdown of these proteins. We already know it’s linked to a process called autophagy, which acts as a garbage disposal system inside our cells. We are looking at exactly how autophagy is increased, and if this can be used as a mechanism to clear toxic proteins across a large number of dementias, first by looking at fly models, and then human, patient derived cells.

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Project 2 - Down Syndrome's and Alzheimer's Disease

in collaboration with Frances Wiseman Laboratory UCL DRI

 

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.

 

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Project 3: Cell death in neurodegeneration
in collaboration with Adrian Isaacs Laboratory and Carlo Sala Frigerio Laboratory, UK DRI

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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?

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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.
 

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Project 4: Mitochondria in Amyotrophic Lateral Sclerosis and Frontotemporal Dementia
In collaboration with Nick Lane Laboratory GEE, UCL

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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).

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Project 5: Metformin in Alzheimer's disease

In collaboration with Selina Wray Laboratory IoN, UCL

Metformin is a drug used to treat type II diabetes has shown promise both as an anti-ageing drug and as a drug to treat a number of diseases associated with ageing, most notably a number of cancers. Its role in Alzheimer’s disease (AD) however is controversial. We have shown that metformin can dramatically ameliorate the climbing and lifespan phenotypes associated with a Drosophila melanogaster model of Aß toxicity, without effecting the levels of Aß peptide. We propose toidentify the molecular pathways responsible for this rescue by screening candidates using Drosophila models of AD. The pathways identified will be confirmed in our fly models and in primary cells line derived from AD mouse models.

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