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The University of Southampton
BRAIN UK

Lay Summaries of studies supported by BRAIN UK by category: Genetic Disorders

BRAIN UK Ref: 11/006
Comparative study of the neuropathology in Huntington’s disease brains
Prof. S B Dunnett, Cardiff University

Huntington’s disease is a genetic disease characterized by progressive motor, cognitive and psychiatric impairment typically manifesting during mid-life. The scale of the defect to the affected gene correlates to the loss of brain cells and therefore to disease severity and age of onset. Cellular loss is particularly evident in an area of the brain called the striatum and this is semi-quantitatively classified using the Vonsattel grading system. However, as HD progresses other areas of the brain are affected by the disease process and there is a sparsity of current information regarding the progression of HD in these areas.

This study aims to use HD brain tissue which has been stratified according to Vonsattel grade with matched controls. Staining methods will be used to determine the spread of HD neuropathology throughout the brain, quantify the degree of genetic damage and determine the processes underlying cell death in HD.

Project Status: Closed

Research Outputs: Grant Application; Presentation

BRAIN UK Ref: 12/006
The impact of mitochondrial DNA mutations on substantia nigra neurons
Dr N Lax, Newcastle University 

Mitochondria are cellular batteries that convert the food we eat into energy, in the form of ATP. They are small complex structures present in every cell in the human body, except red blood cells, and typically, we have many thousands of mitochondria in every cell. Each mitochondrion contains their own small, circular genome (often referred to as mitochondrial DNA or mtDNA) which is made up of genes. These genes are important because they encode for 13 proteins which comprise the mitochondrial respiratory chain. These proteins within the mitochondrial respiratory chain perform complex reactions which allow energy to be formed.
Genetic defects (mutations) within mtDNA mean that these mitochondrial respiratory chain proteins may be produced at lower levels or in extreme cases, not at all. This has a critical impact on the amount of energy which is generated and can result in a number of serious diseases, called mitochondrial diseases. These diseases often affect the brain, nerve and muscles since they tissues have a high requirement for energy. Evidence of mitochondrial dysfunction and damage to the brain nerve cells is frequent in patients with mitochondrial disease and causes severe neurological symptoms. By studying post-mortem tissues donated from patients with mitochondrial disease, we can try to understand the processes leading to neural dysfunction and cell death in order to develop targeted therapies to prevent neurological disease.

Project Status: Active

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BRAIN UK Ref: 13/011
DNA polymorphisms in mental illness (DPIM)
Dr A McQuillin, University College London

We are interested to understand whether there is a genetic basis for susceptibility to Wernicke Korsakoff’s Syndrome (WKS). This syndrome has a number of symptoms including short-term memory loss and in extreme cases psychosis. WKS is thought to be the result of a dietary deficiency of vitamin B1 which is also known as thiamine. WKS can be brought on by malnutrition but in the Western world it is often associated with chronic alcohol misuse. It is currently unclear why some people who chronically misuse alcohol develop WKS whilst others do not. If WKS is identified early enough then it is entirely treatable with intravenous administration of large doses of thiamine. The purpose of our study is to investigate genetic effects that may influence an individual’s susceptibility to the syndrome. This knowledge may have the potential to inform clinical practice in terms of identifying alcohol misusers at greatest risk of developing WKS prior to the onset of symptoms.

Project Status: Active

Research Outputs: Poster x 2

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BRAIN UK Ref: 15/002
Investigating cortical development in Trisomy 21
Dr. R Livesey, University of Cambridge 

Down syndrome is the most common form of intellectual disability, with a worldwide prevalence of 1 in 750 live births. In the majority of cases, Down syndrome is caused by the presence of an extra copy of chromosome 21, so that people have three copies of that chromosome, instead of two – referred to as trisomy 21. To date, little is known about how the brains of individuals with Down syndrome develop and how this may lead to intellectual disability. Using human stem cells, we developed technologies to replay how nerve cells of the main part of the brain that is affected in learning disability, the cerebral cortex, are formed during development. When we compared stem cells with trisomy 21 with those with the normal number of chromosomes, we found a major difference in how many cerebral cortex neurons are produced during development, as well as a lack of specific cell types. Our observations using stem cells in the lab predict that there are changes in the numbers and types of cells made in the developing cerebral cortex in trisomy 21, which could contribute to learning disability. In order to confirm this, we would like to analyse the numbers and types of neurons in the developing cerebral cortex in Down syndrome/trisomy 21, compared with the cerebral cortex with the normal number of chromosomes. This work could lead to a significant advance in our understanding of brain development in people with Down syndrome, and how this contributes to learning disability.

Project Status: Closed

Research Outputs: Poster

BRAIN UK Ref: 15/008
Study title: Investigating the role of Astrocytes and Microglia in the development of Alzheimer's Disease in Down Syndrome
Dr K Murai, McGill University, Canada 

The research to be conducted aims to determine how non-neuronal cells in the brain contribute to the detrimental events in Alzheimer’s Disease (AD) and Down syndrome (DS)-associated AD. A common feature in AD is the recruitment of non-neuronal cells, known as astrocytes and microglia, to areas of neuropathology. Studies are needed to resolve the role of these cells during early, intermediate, and late stages of AD. Using postmortem human tissue of Down syndrome patients, known to develop AD after the age of 45, our preliminary results show the involvement of glial cells in AD-related pathology. This next step of the research will be to determine how glial cells are altered during different phases of AD and DS-related AD using postmortem human tissue. From a therapeutic perspective, this proposal will provide new insight into how regulation of glial cells in the brain may provide an effective target for reducing AD-related pathology in DS.

Project Status: Active

Research Outputs: Abstract x 2

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BRAIN UK Ref: 16/001
Investigation of the role of the c-MET proto-oncogene and the PI3K/AKT/mTOR pathway in brain metastasis.
Prof. Carlo Palmieri, University of Liverpool 

Breast cancer (BC) is the second most common cancer diagnosed worldwide. The most severe form of BC occurs when it spreads (metastasis) from the breast tissue to other regions of the body such as liver, lung, bone and brain. Breast cancer brain metastasis (BCBM) is high despite the performance of current treatments and unfortunately, is incurable. Therefore, it is necessary to try and understand the metastatic machinery that directs breast cancer cells to the brain and helps them establish BCBM. The machinery (human genome) that controls our cells, is composed of different tools (known as genes and proteins) that communicate and regulate each other forming a pathway. Any changes on these tools can affect their interaction and alter their pathway leading to cancer development and metastasis. This project aims to investigate further how these changes lead to communication problems between genes and pathways in brain metastasis by using a large number of BCBM cases. This knowledge will helps us to improve treatment selection and facilitate the development of new drugs.

Project Status: Active

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BRAIN UK Ref: 16/002
Multi-platform analysis of TSC Subependymal Giant Cell Astrocytoma (SEGA) to identify novel therapeutic approaches.
Dr Eleonora Aronica/Dr Angelika Mühlebner), Academic Medical Centre, Amsterdam 

Tuberous Sclerosis Complex (TSC). TSC is a genetic disease which causes multiple tumours within the body. Heart, brain, kidney, skin and lung can be affected. Subependymal giant cell astrocytoma (SEGA) are benign tumours. These grow slowly but constantly in brains of the patients. In children they are one of the more common causes of complications associated with the disease. This leads to brain swelling (increased intracranial pressure) and all associated risks. The treatment of the tumour usually means surgery or medication with so-called mTOR-inhibitors. These are specific types of medications targeting the mTOR complex which is the main affected protein complex in TSC. However, little is known about how these tumours grow and why some of them are more responsive to medication than others. Therefore, we use a battery of modern techniques to gain insights in the development of these tumours and unravel novel therapy strategies.

Project Status: Active

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BRAIN UK Ref: 16/012
DNA/RNA instability in spinal muscular atrophy
Profs. M Azzouz & S. El-Khamisy, University of Sheffield 

Spinal muscular atrophy (SMA) is severely debilitating and ultimately life-limiting conditions that selectively affect motor neurons, the nerve cells that control our voluntary muscles. People affected by motor neuron diseases lose the ability to walk, move, talk, and finally breathe. Currently, there is no cure or therapy to treat these devastating diseases effectively, as the precise mechanisms that cause motor neuron diseases are still poorly understood. The aim of our research therefore is to identify key disease mechanisms and targets to accelerate the development of much-needed treatments for motor neuron diseases.

This research project is based on our compelling results that links nerve cell injury to damage in the molecule that carries the genetic information (DNA) in all the cells. The studies proposed will use a multidisciplinary approach to explore the exact role of the gene causing Spinal muscular atrophy in DNA damage. Using experimental models and human tissue, these studies should create significant insights into the mechanisms behind motor neuron injury and identify key targets and new strategies for the development of effective treatments for motor neuron diseases. Moreover, these insights should also benefit and improve outcomes for other related and currently untreatable disorders caused by the damage and loss of nerve cells.

Project status: Active

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BRAIN UK Ref: 17/011 
Tau and A2AR expression in Alexander’s disease
Prof Delphine Boche, University of Southampton 

Alexander’s disease is a rare terminal disease mostly affecting children.  The disease is in a group of brain cells called astrocytes and a genetic link has been identified as the cause.  However, little is known about how the genetic problem leads to disease. 

One hypothesis is that astrocytes lose their ability to control glutamate level, a key chemical for the communication between brain cells.  As a result, patients with Alexander’s disease have an increased quantity of glutamate in the brain, which could explain the epilepsy observed in the patients.  The high amounts of glutamate increases the development of protein tangles in the brain and brain inflammation.  This protein, known as Tau, is involved in the communication between the cells.  The inflammation also increases Tau impairment.  This study will investigate the astrocytes role in the development of Tau protein tangles in Alexander’s disease patients and its relation to the development of brain inflammation.

Project status: Active

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BRAIN UK Ref: 18/007 
Charcot-Marie-Tooth Disease and related disorders:  A Natural History Study
Prof. Mary Reilly, University College London Hospitals (UCLH) NHS Foundation Trust

CharcotMarieTooth Disease (CMT) is the most common cause of inherited peripheral neuropathies affecting approximately 1 in 2500 people. People with this condition present with upper and lower limb weakness, wasting and sensory loss as a result of degeneration of the long peripheral nerves supplying the muscles. Despite the clinical similarities among patients with CMT the group is genetically very different.

Advances have been made in identifying the genes that cause CMT. However, the best way to treat the different variants of this disorder is not known. In addition, we don't have natural history data of most forms of inherited neuropathies.

We are currently doing a wider study to characterise the features of different types of CMT, the long term progression of the disease and how some specific gene mutations can cause the neuropathy. We will supplement the study with some cases of CMT from BRAIN UK.

Project status: Active

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BRAIN UK Ref: 18/011 
Investigation of cerebellar ataxia
Prof Henry Houlden, University College London

Cerebellar ataxia is a neurological problem in which patients complain of poor balance, have movement problems, demonstrate abnormal eye movements and also have speech and swallowing problems.

For a proportion of these ataxias there is a known fault in the genetic make-up which is the reason why this neurological problem develops in these patients, but for some the underlying cause is not known.

We have recently identified a new genetic defect in a small group of patients with ataxia. We want to investigate if muscle and nerve biopsies from these patients can tell us anything important about the underlying mechanisms. We want to see if there are any correlations with the pathological alterations observed in these patients and those without the genetic defect.

We hope that this study will help us to understand further the underlying mechanisms leading to ataxia and neuropathy development, which we hope will help diagnose the disease more accurately.  

Project status: Closed

 DatePublication title
2019 Biallelic expansion of an intronic repeat in RFC1 is a common cause of late-onset ataxia.

BRAIN UK Ref: 19/008 
C1q in Huntington’s disease
Prof Roxana Carare, University of Southampton

Huntington's disease is a devastating genetic progressive brain condition with no cure, that affects people in their young adult life who develop uncontrolled movements, emotional and thinking problems. A key feature in Huntington’s disease as in many other brain diseases is inflammation. A product of inflammation is C1q which triggers a cascade of events that harm the brain. We want to test whether a new compound (antibody) that is developed against C1q is specific to the C1q in Huntington’s disease human brains. Annexon Biosciences is a company that has developed the compounds that target C1q that seem to have favourable effects in other neurological conditions. We propose to compare the Annexon compounds against commercially available markers of C1q in a very small set of 3 Huntington’s disease brains. If the results appear meaningful, we will increase the size in a future study with statistical power and we will also complement with other experimental methods in the lab. Long term, the aim is to develop the antibodies against C1q produced by Annexon, to ameliorate/slow down the progression of Huntington’s disease. 

Project status: Active

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BRAIN UK Ref: 19/014
PURA syndrome patient tissue sample banking for histopathological and molecular analysis
Dr Jennifer Gordon, Temple University Philadelphia 

PURA syndrome is a rare disorder in which development of the brain in young people causes them to have development problems, which include movement and learning ability. This disorder is caused by mutations, which is a change in the DNA sequence, in the Pur-alpha gene (PURA). Currently there are no treatments, except managing the disease, which causes difficulty in mobility, learning difficulty and epilepsy. Patients with the disease, require lifelong care, including in day to day activity. The way the mutation in the PURA gene occurs is not known currently.

In my lab we have been able to recreate an experimental mouse model that mimics the PURA syndrome and we have shown the mutation in the brain and other organs, similar to humans. In this study, we plan to use left over, and archived brain and other tissue from PURA syndrome and normal patients, to study the disease. We will look at levels of Pur-alpha and other associated genes, in normal and PURA syndrome tissue. This could lead to finding out, how the mutation occurs, and in the future, may lead to treatment, that could either reverse this or stop it all together. 

Project Status: Active

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BRAIN UK Ref: 19/019
Social Neuropeptide Dysfunction in Fragile X Syndrome
Veronica Martínez-Cerdeño, University of California

Lay summary is not available

Project Status: Active

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