The neuroscience theme embraces neurology research, across the whole translational spectrum from basic science to clinical trials and is funded by MRC, BBSRC, Wellcome, CR-UK and NIHR. Our research is disease orientated and looks at underlying mechanisms such as cell death and stem cells helping to understand the disease areas we focus on i.e. neurodegenerative diseases as well as disorders of myelinating cells, ischemia and brain tumours. Neurodegenerative diseases include Multiple Sclerosis, Alzheimer's, Motorneurone and Parkinson's diseases. Our aim is to develop new treatments for these potentially devastating conditions, and test treatments in clinical trials using the best methods available. This involves developing new ways of doing clinical trials, linked to a programme of laboratory research in neurodegeneration.
Finding new drug targets and new targeted therapies through understanding the disease mechanism and then translating these new treatments into the clinic is our focus.
We have strong links with PU PSMD other research themes especially Infection, Immunity and Inflammation, Diagnostics and Cancer. We are also part of the faculty-wide research into clinical neuroscience.
Overexpression of KSR1 active mutant in Schwann cells changes them to a tumour-like multipolar morphology. Image copyright (C) 2014 Lu Zhou
Role of mitochondrial dysfunction in disease
Like all living organisms, we humans need to extract energy from our environment to escape death and the cellular mechanisms by which this energy is transduced and conserved are thus critical to our survival. As the powerhouses of the cell, mitochondria play a key role in cellular bioenergetics and mitochondrial dysfunction has indeed been linked to a range of diseases. Research in the Affourtit Lab aims to establish the role of bioenergetic failure in the Metabolic Syndrome, a cluster of medical disorders that collectively increase the risk of developing type 2 diabetes and cardiovascular disease. Current projects explore how mitochondria may mediate obesity-related defects in insulin secretion by pancreatic beta cells and in the insulin sensitivity of skeletal muscle.
Understanding mechanisms of insoluble protein aggregates formation and cellular degeneration in the human brain is one of the most pressing questions of clinical neurobiology. We are trying to understand the process of alpha-synuclein aggregation in the development of neurodegenerative disorders such as Parkinson's disease and dementia with Lewy bodies. In particular, we are looking for the reasons of a selective vulnerability of neurons to the toxic insult caused by aggregating proteins and whether dis-aggregating strategies could be beneficial in these conditions. To address this, classical neuromorphology, biochemistry and cell biology techniques are used in a range of in vitro and in vivo models, including human post-mortem studies, animal models of neurodegeneration and cell culture assays.
Neural Stem Cell Regulation and Development in Health and Disease
The controlled generation of new neurons and glia cells in the brain from Neural Stem Cell (NSC) progenitors is crucial not only during embryonic development but throughout adult life. Deregulation of adult NSCs impacts on normal brain function and can lead to a variety of brain disorders. The development of NSC-based therapies holding promise towards replacement of dying or malfunction brain cells, and more effective brain tumour treatments, depend on our understanding of how NSCs are regulated. Our team research focus is to reveal and understand the signals controlling post-embryonic Neural Stem Cell mitotic activation, cell fate and lineage maturation in both normal and pathological conditions, such as during brain tumour formation. We take advantage of one of the best in vivo genetic models available, the Drosophila central nervous system, and seek to translate our findings to vertebrate systems, including the human brain.
Image shows Neural Stem Cells (green, GFP) inside the Drosophila brain, some about to proliferate (red, CyclinB)
Repairing nerve damage
Understanding the workings of the human central nervous system (CNS) with its millions of neurons generating trillions of connections is a formidable challenge. Fortunately, to uncover the basic rules, we can turn to simpler organisms. I am using the simple fruit fly Drosophila to study evolutionary conserved mechanisms in CNS development and disease. Using classical genetics, molecular biology, transgenics and micromanipulation I study the embryonic development of the CNS to understand how damage to it can be repaired. I also investigate the transcriptional program that ensures the correct formation of neural networks controlling movement.
Image shows ventral nerve cord of Drosophila embryo
White matter inter-connects the complex human cerebral cortex. It makes up 50% of our brains and contains axons, which mediate action potential conduction, and glial cells, which support the axons. The brains of rodent models of disease contain much less white matter than does the human brain and heavy use of these models has therefore grossly under-estimated the significance of white matter pathology to human health. White matter represents a poorly understood frontier in the science of brain disease and the Fern laboratory focuses on disorders arising from loss of blood supply (ischemia) such as stroke and cerebral palsy, but white matter is relevant to almost all major neurological disorders.
My research is on neuromuscular disease, especially motor neuron disease and neurooncology. Current work on motor neuron disease is mainly clinical and includes genotype-phenotype analysis and clinical trials. In neurooncology we focus on cell biology studies to find and validate new therapeutic targets as there is a great medical need to find new treatments.
I lead our brain tumour research team, who make up one of four UK Brain Tumour Research Centres of Excellence supported by the charity Brain Tumour Research.
Molecular networks in neurodegeneration
Neurodegenerative diseases such as Alzheimer’s, Parkinson’s and Huntington’s disease are characterised by a wide range of symptoms and underlying molecular processes. The observed heterogeneity on geno- and phenotypic level makes it difficult to understand fully the progression of neurodegeneration and to find cures. To connect the different neuropathological features and consolidate different experimental findings, we develop and apply tools of integrative network biology in our study of neurodegeneration. Application of these tools enable us to obtain models of molecular networks that link the different relevant processes and that give us a more holistic view of neurodegenerative diseases. Ultimately, we aim to explore the network models for the discovery of new ways to treat effectively neurodegeneration in the human patient.
Image shows networks associated with Huntington's disease (F1000Research. 2016. 4:103)
Parkinson’s and related diseases
Alterations in cell surface protein signalling have been implicated in the pathogenesis of neurodegenerative disorders such as Parkinson disease (PD), Alzheimer disease (AD) and motor neuron diseases, but also in diseases such depression, attention-deficit/hyperactivity disorder (ADHD) and schizophrenia. My research group focuses on investigating the cross-talk and function of the glial cell-line derived neurotrophic factor (GDNF) receptors in the nervous system. In addition, we analyse the function of different intracellular proteins encoded by genes mutated or linked to PD. We study their signalling mechanisms on a molecular and cellular level as well as in rodents.
Dopaminergic neurons stained with antibodies against tyrosine hydroxylase in coronal midbrain sections of the mouse
Genetics of psychiatric disorders
My research focuses on the genetic architecture of psychiatric and neurological disorders, in particular bipolar disorder. Such complex disorders are highly polygenic and thousands of genetic variants are likely to be causing susceptibility to these disorders. We study both common and rare genetic variants, including single nucleotide polymorphism and structural variants such as copy number variations, and more recently retrotransposons. In collaboration with Cardiff University through the National Centre of Mental Health we have access to large samples and datasets including vast phenotype information which allows us to study subsets of the bipolar sample, such as postpartum psychosis, schizoaffective disorder and co-morbid migraine.
Autophagy is an intracellular bulk degradation system mediated by lysosomes, and its substrates include long-lived cytosolic proteins, intracellular pathogens and damaged organelles. Autophagy is involved in many biological processes of normal physiology, such as mitigating metabolic stress, degradation of aggregate-prone proteins (e.g, mutant huntingtin), and tissue homeostasis. Defects in autophagy process are associated with numerous pathophysiologies, including neurodegenerative diseases and tumorigenesis. The research in our lab currently focuses on autophagy regulation and its roles in neurological diseases.
The biology of Schwann cells in the peripheral nervous system
My research interest is in the control of myelination and repair in the peripheral nervous system (PNS). The PNS is myelinated by Schwann cells which ensheath and myelinate the large caliber axons and allow rapid (saltatory) conduction of nerve impulses. Most recently I have begun to investigate what underlies the remarkable ability of Schwann cells to regenerate and repair injury in the peripheral nervous system and how proteins such as c-Jun and Sox-2, both transcription factors, facilitate this repair and cell plasticity. Loss of the tumour suppressor Merlin causes tumours of Schwann cells, schwannomas, and we are also interested in the initiation events and changes in cell signalling that occur in these tumours.
TEM showing (dark) Schwann cells surrounding axons