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The University of Southampton
BRAIN UK

Lay Summaries of studies supported by BRAIN UK by category: Developmental

BRAIN UK Ref: 10/002
White matter disorders in children: from magnetic resonance to basic defect
Prof. M S van der Knaap, Amsterdam 

Lay Summary not available. 

Project status: Closed

BRAIN UK Ref: 11/005
Fight Alpers’
Prof R W Taylor, University of Newcastle 

Alpers’ syndrome is a rare progressive disease typically of childhood characterized by seizures, mental retardation, blindness and liver failure. It is caused by a defect in a gene present in subcellular elements called mitochondria leading to their dysfunction in the central nervous system and liver. Given the rapid onset of symptoms and a lack of cure diagnosis needs to be rapid in order to better manage the debilitating symptoms of this disease.
As Alpers’ syndrome is rare there is limited knowledge of the neurodegenerative changes that occur. An increased understanding of the pathological processes will ultimately allow the development of better treatment strategies for affected patients. The applicant will use an array of special staining methods on tissue from Alper’s syndrome patients in order to determine any link between brain pathology, mitochondrial dysfunction and clinical symptoms exhibited.

Project status: Closed

Research Outputs: Publication; Abstract; Presentation x 2; Poster x 2

DatePublication title
2018 Dissecting the Neuronal Vulnerability Underpinning Alpers' Syndrome: a Clinical and Neuropathological Study

 

BRAIN UK Ref: 13/005
UK brain bank for autism and other developmental disorders
Prof. O Ansorge, University of Oxford 

A hugely varying range of impairments and abilities are associated with normal and abnormal development of our brain. Autism spectrum disorder (ASD) in its most severe form can be very disabling. Compared to neurological disorders of aging, such as Alzheimer’s, very little is known about the biology and pathology of normal and abnormal development. The aim of the UK Brain Bank for autism and related developmental disorders is to further our understanding of the cellular, biochemical and genetic correlates of normal and abnormal development of the human brain. This can only be done by studying tissue generously donated after death. The tissue bank is hosted in Oxford and integrated into the wider Oxford Brain Bank and a network of Brain Banks in the USA. We have an agreement with Brain UK to make available to national and international researchers any brain tissue relating to autism and other developmental disorders collected in the UK in order to further our understanding of fundamental principles of human brain development.

Project status: Closed

BRAIN UK Ref: 13/006
Characterizing microglia/macrophage polarization in paediatric brain injury
Dr V Miron, University of Edinburgh 

Our research centres on finding out more about how brain damage develops in babies with cerebral palsy and investigating the natural processes that are involved in brain repair. We focus on the role of cells called macrophages in damage to, and repair of, a substance called myelin. Myelin forms a protective coating around nerve fibres in the brain to allow nerve function and health, but it can be damaged in babies with cerebral palsy. Our previous studies investigating myelin repair in the brain of adults showed that macrophages need to be activated in a specific way in order for this repair to occur. In this study, we are investigating whether damage in brain tissue of babies who would likely have gone on to develop cerebral palsy is linked to low levels of these activated macrophages. We also aim to identify substances released by macrophages that stimulate brain repair, as it’s possible these substances could form the basis of new medicines.

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: 17/009
Investigating the role of extracellular matrix in human neocortical development.
Prof Wieland Huttner, Max Planck Institute of Molecular Cell Biology and Genetics, Dresden, Germany 

The cerebral cortex is the major centre for cognitive processes, including memory, awareness and language, and is arguably an integral part of what makes us human. Understanding the mechanisms behind its development and function are vital to understand, and therefore treat, the many developmental disorders, diseases and injuries that affect it. Currently there are relatively few treatments available as our understanding of neocortical development is far from complete. To address this gap in our knowledge we require further insight into the regulation of neural stem cell (NSC) behaviour and function. Despite recent advances in the field, relatively little is known about the regulation of NSCs when compared to other systems, such as blood, due to the location and complexity of neural tissue and development. We aim to investigate the role of extracellular matrix (ECM) proteins in the development of the human cortex and NSC behaviour. ECM proteins usually reside outside of cells within the tissue and have many roles, including providing a supportive structure for the cells to reside in and maintain tissue shape and integrity. Recent studies have shown that ECM may also provide instructive signals, directing cell behaviour and influencing cortical development – specifically in the increased generation of neuronal cells required for the expansion of the human cortex. We aim to study the role of ECM in the regulation of NSC behaviour and the development of the complex human cortex.

Project Status: Active

Research Outputs: Publication x 1; Abstract x 1; Presentation x 16

DatePublication title
2018 Extracellular Matrix Components HAPLN1, Lumican, and Collagen I Cause Hyaluronic Acid-Dependent Folding of the Developing Human Neocortex
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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: 17/016
Understanding the mechanisms contributing to epileptogenesis in Alpers’ disease
Dr Nichola Lax, Newcastle University

Alpers’ syndrome is a rare progressive disorder which typically affects young children (6 months to 3 years) and is characterised by severe epilepsy, loss of developmental skills and liver failure. Alpers’ syndrome may develop when the cellular batteries, known as mitochondria, do not work properly. More specifically, Alpers’ is caused by a fault in Polymerase Gamma, an enzyme that allows the mitochondrion to make its own DNA (mtDNA). This defect was not discovered until 2004 when researchers found faults in a gene called POLG, which contains the genetic code for Polymerase Gamma. In Alpers’ syndrome the faulty Polymerase Gamma does not make sufficient mtDNA in brain or liver and so these organs become depleted of mtDNA. This loss of mtDNA contributes to fatal neurodegeneration and liver failure however there is limited understanding of the precise mechanisms underpinning these changes. Since the onset of symptoms is rapid, and there are no cures for Alpers’ disease, this project aims to further our understanding about disease pathogenesis in order to explore potential avenues for the development of targeted therapies. We are specifically interested in exploring the link between the devastating seizures, brain pathology and mitochondrial dysfunction in post mortem tissues from patients with Alpers’ syndrome.

Project Status: Active

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BRAIN UK Ref: 18/012
How the matrisome drives human neocortex folding during development and neurodevelopmental disorders
Dr Katherine Long, Kings’ College London

The neocortex (the outer part of the brain) is the seat of many of the higher cognitive functions that make us human, such as our memory, speech and advanced learning. How the neocortex controls these functions remains an open question.

Evidence from patients with developmental disorders suggests that the correct shape of this part of the brain is vital for these functions, especially the correct folding of the neocortex (which gives the brain its wrinkled appearance). These folds are almost identical in every person, and alterations in either their number or location can lead to cognitive defects.

Despite their importance, very little is known about how folds form during human brain development. I will combine state-of-the-art and innovative methods to study the mechanisms that regulate folding of the human neocortex. This will allow me to probe how folding normally develops, and how alterations cause folding disorders, using human neocortex tissue.

Project Status: Active

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