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The University of Southampton

Lay Summaries of studies supported by BRAIN UK by category: Neurodegenerative Disorders (Other).

This includes all neurodegenerative disorders except Alzheimer's Disease which has been given a separate section.

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: 12/004
Evidence for stem cell neuroprotection in genetic ataxias
Dr K Kemp, University of Bristol 

Within the cerebellum, one particular cell, the Purkinje cell, is crucial to its overall function and is progressively lost in many neurological diseases, including the inherited cerebellar and spinocerebellar ataxias. Finding a way of protecting this cell specifically is therefore of vital importance to prevent progressive disability. Studies clearly indicate bone marrow-derived cells protect nerve cells and induce repair of the nervous system. They do this by multiple mechanisms, but one important process that has been observed is called cell fusion. Cell fusion being when genetic material (DNA) from one cell becomes integrated into another cell. The phenomenon of bone marrow-derived cells fusing with Purkinje cells has been observed in experimental models of cerebellar disease, raising the possibility that fusion is a repair process to rescue damaged nerve cells. The aim of this project is therefore to explore in human tissue donated from patients who had a history of genetic cerebellar or spinocerebellar ataxia, whether stem cell recruitment and Purkinje cell fusion in the brain is influenced by their disease. In-turn, we hope the proposed studies will help provide novel and fundamental insights into the ways in which nerve cells can be protected or replaced.

Project Status: Active

Research Outputs: Publication; Grant Application x 2; Abstract; Presentation x 5

DatePublication title
2016 Purkinje Cell Injury, Structural Plasticity and Fusion in Patients With Friedreich's Ataxia
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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: 12/007
Regulation of microglial proliferation and its contribution to chronic neurodegeneration
Dr D Gomez-Nicola, University of Southampton

Lay Summary not available.

Project Status: Closed

BRAIN UK Ref: 12/008
Protein conformation changes in chronic traumatic encephalopathy and other tauopathies
Dr I Caesar, Mount Sinai School of Medicine, New York

Lay Summary not available.

Project Status: Closed

BRAIN UK Ref: 13/001
Are neurodegenerative diseases and gliomas inverse comorbidities?
Dr F Roncaroli, Imperial College, London

The study of the association of different diseases and how they influence each other has proved a promising venue to elucidate the mechanisms underlying several common conditions such as diabetes, cancer and brain degeneration. “Comorbidity” is used when one disease occurs at higher frequency than normal in patients that already have a common condition and “inverse comorbidity” when one disease occurs at a lower than expected frequency in people with a common condition. Patients with degenerative conditions of the brain such as Alzheimer’s disease and Parkinson’s disease often have lower occurrence of cancer than the any other individual of similar age. This evidence led to suggesting that patients with brain degeneration are somehow protected to developing cancer.

The most common and most aggressive brain tumour is called glioblastoma. It occurs at any age but it is vastly more frequent between 50-70 years. Glioblastoma is a killer. Patients with this form of cancer rarely survive longer than 12-14 months form the time the tumour is diagnosed. Cancer cells that constitute glioblastoma can interact with the cells of the normal brain and exploit them to better survive, grow and invade the surroundings.

At the UK Parkinson’s Disease tissue bank at Imperial College, London, we have observed that patients with Parkinson’s disease are unlikely to develop glioblastoma. Such observation was supported by the analysis of death certificates in the UK documenting a much lower than expected occurrence of glioblastoma in patients who died of Parkinson’s and Alzheimer’s disease.

This study aims to understand if the brain affected by degenerative conditions has anything that stops glioblastoma to develop. We have therefore enquired Brain UK to run a survey of the over 36,000 records available for the association between Parkinson’s and Alzheimer’s disease and glioblastoma.

Project Status: Closed

Research Outputs: Abstract

BRAIN UK Ref: 14/007
Pilot study: Expression of Bim in Huntington’s Disease
Dr. S Luo, University of Plymouth

Bim is a BH3-only pro-death protein that is essential for apoptosis (a form of cell death) when cells are induced by death stimuli, and it is crucial in neuronal cell death in pathological conditions. Recently we found that Bim inhibits autophagy, a self-eating process in cells. Therefore, Bim is a key molecule with dual roles in regulating autophagy and apoptosis. This suggests that Bim is a potential target to tackle neuronal cell death and neurodegeneration, since autophagy has neuroprotective roles and apoptosis is a major mechanism for neuronal death. Therefore, it is attractive to investigate if Bim levels are increased in neurodegenerative diseases such as Huntington’s Disease (HD). We aim to test if Bim levels alter in the pathological conditions in HD versus control brains. The levels of Bim mRNA from HD brain subjects (striatum and cortex) and age-matched healthy brain tissues will be examined using quantitative RT-PCR (qPCR) assays. Bim protein levels are also to be tested in the settings using immunohistochemistry and immunoblot to complement the qPCR data. This study will potentially reveal a new therapeutic target for the disease.

Project Status: Active

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BRAIN UK Ref: 15/020
Studying the turnover of oligodendrocytes in Huntington's disease.
Dr M Djelloul, Karolinska Institute, CMB, Stockholm 

Huntington’s disease is a neurological condition that is devastating to the patients but also to their family. The onset occurs in the prime of adult’s life. The patients lose control of their movements and other complications occur such as pneumonia and heart disease. It usually ends up with dementia. It is now well established that the disease is caused by a mutation in a gene encoding for the protein Huntingtin. This latest is involved in neuronal development. It has been shown in Huntington’s disease that the mutated form of Huntingtin accumulates in the cells of the body and forms aggregates. This is linked to the severity of the disease. In our laboratory, we use a technique based on Carbon-14 dating to measure the ability of different regions of the brain to regenerate. We have been able to show recently that neurons have a slower turnover in Huntington’s disease. We would like now to extend our study by analyzing other cell types such as the oligodendrocytes as these are the most vulnerable ells of the central nervous system.

Project status: Active

Research Outputs: Presentation

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BRAIN UK Ref: 16/005
Consensus diagnostic criteria of a novel tauopathy associated with anti-IgLON5
Prof. T Revesz, University College London 

In this disease degeneration of nerve cells takes place in parts of the brain, which are essential for maintaining fundamental functions such as sleep, respiration and movement. This is due to the accumulation of a protein, called tau in the form of insoluble filaments within nerve cells and their processes of specific brain and spinal cord areas. Interestingly in individuals with this disease an antibody can be identified in the blood, which is produced by the affected individual’s immune system (autoantibody) against a protein, called IgLON5, present on the surface of nerve cells. 

Our project aims to establish the neuropathological diagnostic criteria of this novel, devastating neurological disease. At the UCL Institute of Neurology two such cases has so far been identified to have the post-mortem findings of anti-IgLON5 antibody-related tauopathy. We would like to use these two cases for this research.

Several neuropathologists working in three different European neuroscience centres met in September 2015 and agreed on the details of this project. The experts agreed using unified criteria for the neuropathological study and the comparison of the six cases, which are currently available in the three European centres.

We expect that this project will allow us to propose neuropathological diagnostic criteria of this novel disease, which can be validated in the future. We wish to publicise our findings for the wider neuropathologist community in the form of a scientific paper. 

Project Status: Closed

Research Outputs: Publication

 Date Publication Title
 2016  Neuropathological Criteria of anti-IgLON5-related Tauopathy 

BRAIN UK Ref: 16/010
Selective vulnerability in MND/FTD
Dr O. Ansorge, University of Oxford 

Motor neuron disease (MND) is a progressive neurodegenerative disorder that destroys motor neurons, the cells that carry the signal for muscle movement such as speaking, walking, breathing, and swallowing. There are different types of motor neurons which can be grouped depending on whether they are carrying signals around the brain and spine (upper motor neurons) or from the spine to the muscles (lower motor neurons). They can be further grouped depending on whether they are signalling fast acting or quickly fatiguing movements. Certain groups of neurons are affected differently during the course of motor neuron disease. The most significant degeneration (decline) of neurons in MND occurs within the spinal cord, however there is also moderate loss of upper motor neurons in the brain and spine.

We are particularly interested in upper motor neuron vulnerability. To investigate this, we will look for proteins that characterise neuron subtypes in conjunction with proteins that charcterise the disease effects, to identify whether particular neurons are more likely to collect disease-related proteins.

Project Status: Closed

Research Outputs: Presentation, Poster

BRAIN UK Ref: 17/001
Pathological study of two cases with SLC52A3 mutation
Prof Tamas Revesz, University College London

Brown-Vialetto-Van Laere syndrome is a rare neurological disorder, named after three scientists, who first described this devastating condition.  It affects the body’s nervous system.  In this disease, degeneration of the nerve cells takes place in parts of the brain which are essential for maintaining fundamental functions, such as movement and breathing.  Most patients die at a young age because of the destruction of vital centres in the brain. 

Recently, mutations in several genes have been identified in a group of patients with this syndrome. A gene is the basic unit of heredity, which determine the characteristics you inherit from your parents.  Genes, which are made up of DNA, act as instructions to make molecules in the body called proteins.  The proteins encoded by the mutant genes are known to be involved in normal function of mitochondria – small structures inside the cells, which are the main energy provides (also called powerhouses of the cells).  In this study we are investigating whether the disease changes in the patients with this syndrome mimic the changes seen in patients with mitochondrial diseases.  

Project Status: Closed

Research Outputs: Publication

Date Publication Title 
 2017  Clinical, Pathological and Functional Characterization of Riboflavin-Responsive Neuropathy


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: 17/014
The Dynamics of Microglia in the Human Brain
Dr Diego Gomez-Nicola and Dr David Menassa, University of Southampton

Microglia, the brain’s immune cells, have been proposed to play key roles in brain development and function. Microglia have been described in the brain from the 3rd gestational week, completing their colonization of the embryonic brain by the 22nd week. In adults, it is widely assumed that these brain immune cells are long-lived and are locally replaced. However, the origin and maintenance of the human microglial population is not clear and their precise pattern and growth in the developing and mature human brain are unknown. Therefore, we are proposing to map the microglial population across the human lifespan starting from early embryonic development until old age. Studies of this nature are non-existent and we would be the first to thoroughly describe how these cells populate different brain areas and how age and sex might affect their growth, proliferation and distribution.

Project Status: Active

Research Outputs: Presentation x 3

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BRAIN UK Ref: 19/007
Pathological and genetic study of an unusual case of alpha-synucleinopathy
Prof Janice Holton, University College London 

In a group of diseases known as α-synucleinopathies an abnormally sticky protein called α-synuclein forms clumps inside brain cells causing nerve cells to die. The most common disease in this group is Parkinson’s disease (PD) but there is also a rarer form called multiple system atrophy (MSA). PD and MSA do not usually occur in families but there are rare instances of familial PD caused by alteration (mutation) in the gene that codes for α-synuclein protein. One clue that there may be a mutation in this gene is the finding of an unusual pattern of α-synuclein inclusions when the brain is examined. We have observed an unusual pattern of these changes in a single case and would like to investigate this further to determine whether it is due to a gene mutation. Study of rare cases has often enabled us to have a better understanding of common diseases. We hope that by performing a detailed study of pathology and genetics in this single case we may gain insight into the mechanisms causing PD and MSA. This would be very important for this group of people who have progressive disease with no currently available treatments that can alter the disease course.

Project Status: Active

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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: 19/015
Understanding pathological progression in corticobasal degeneration
Prof. Tamas Revesz, University College London 

Not yet available 

Project Status: Pre-Approval

BRAIN UK Ref: 20/004
Ultrastructural Endoneurial Pathology to Explain the Normal Function of the Human Blood Nerve Barrier and the Pathogenesis of Inflammatory Nerve Disease.
Professor Alison Lloyd, University College London 

Peripheral nerves (PN) communicate information to the brain from surface tissues and back to muscles to make responses. Peripheral neuropathies are conditions in which those nerves can become damaged resulting in numbness, pain or weakness. PN are very small and understanding how the 6 known types of cells within the nerve communicate in health and disease has evaded study. We aim to study nerves in health and in relation to three diseases which are described below. 

CIDP- Chronic Inflammatory Demyelinating Neuropathy
This is a disease whereby the individuals immune system attacks the peripheral nerves (i.e. nerves in the arms and legs) leading to weakness and sensory loss. The immune system damage results in the myelin sheath of the nerve (the ‘insulating’ cover of the nerve which allows the nerve to fire nerve impulses) being damaged which is termed demyelination. This occurs over several weeks to months, and can continue indefinitely if not treated.  

POEMS – Polyneuropathy, organomegaly, endocrinopathy, monoclonal disorder and skin disease.
This is a very rare cause of nerve damage and is the result of an abnormal blood cancer cell leaking inflammation molecules which cause damage to peripheral nerves. This results in the 5 key symptoms of POEMS syndrome- the Polyneuropathy (multiple nerves in the arms and legs damaged), Organomegaly (enlarged organs), Endocrinopathy (hormaon problems), Monoclonal disorder (the blood cancer) and Skin lesions. We believe the inflammation molecules in POEMS syndrome leads to damage and leak at the blood nerve barrier but this has never been studied before. 

Multiple myeloma
Is a similar blood condition to POEMS syndrome but doesn’t cause neuropathy per se and is therefore of interest to compare. 

Professor Lloyd’s team are the first to identify, classify and image the 6 nerve supporting cell types. They have demonstrated through visualisation under highly powered microscopes in mouse and rat nerves how the cells of the blood vessels interact with specialised nerve supporting cells to keep the blood nerve barrier impermeable. They have also discovered how special types of white blood cells important in immune function called macrophages remove potentially damaging substances which enter the nerve through the barrier.

We wish to look at the nerve supporting cell types in specimens from human specimens without disease, and in CIDP, POEMS and myeloma patients. These nerve samples will have already taken and used for clinical diagnostic use. We will use these nerve samples to see if the same appearances of nerve supporting cells, macrophages and blood vessels are present in human nerve and if they are altered in POEMS and CIDP.

POEMS: Polyneuropathy, Organomegaly, Endocrinopathy, Monoclonal plasma cell disorder, Skin lesions
CIDP: Chronic Inflammatory Demyelinating Polyneuropathy

Project Status: Active

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