New blood vessel formation in the peripheral nervous system following injury (David Parkinson group)
New blood vessel formation in the peripheral nervous system following injury (David Parkinson group)
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 Plymouth Institute of Health and Care Research (PIHR) 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
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.

Neurodegeneration dementia

Oleg Anichtchik
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 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 translate our findings to the human brain using human brain cell cultures, tissues and tumour samples.
Image shows Neural Stem Cells (green, GFP) inside the Drosophila brain, some about to proliferate (red, CyclinB).
Image shows Neural Stem Cells (green, GFP) inside the Drosophila brain, some about to proliferate (red, CyclinB)

Damage repair and network formation in the CNS

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, micromanipulation, CrispR/ Cas9 and single cell transcriptomics 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
Image shows ventral nerve cord of Drosophila embryo

Translational Neurobiology

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.
Robert Fern Neuroscience

Molecular basis of neuron-glia communication

My main research interest is molecular basis of neuron-glia communication. Glia cells are the most abundant cell type in human brain. Communication between neuron and glia cells is one of the most intriguing processes that happen in the brain. It is mediated through different classes of receptors and release of small double membrane vesicles called exosomes. Study of these mechanisms can help us to understand molecular basis underlying pathomechanisms of brain disorders like Alexander disease, Alzheimer’s, and Parkinson.
Konstantin Glebov Research

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
Dopaminergic neurons stained with antibodies against tyrosine hydroxylase in coronal midbrain sections of the mouse

Clinical Neurobiology

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 neuro-oncology 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.

Autophagy regulation

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.

Development, repair and tumour formation in the nervous system

My research interests are in the control of myelination and repair in the peripheral nervous system (PNS) as well as drivers of cell proliferation in tumours of the nervous system. We study the biology of the Merlin tumour suppressor and how this protein regulates cell behaviour. We use several different model systems, such as transgenic mouse models and human tumour cell culture, to understand how loss of Merlin, and dysregulation of Hippo pathway signalling, regulates peripheral neve development, PNS repair and how tumours such as schwannomas and meningiomas arise and grow in the nervous system. The identification of new targets for drug treatments may be used to both improve the outcomes of PNS repair as well as novel therapies for nervous system tumours.
TEM showing (dark) Schwann cells surrounding axons

TEM showing (dark) Schwann cells surrounding axons

Protection and repair of central nervous system myelination

The focus of research within my laboratory is centered around molecules that modulate oligodendrocytes and their progenitors, OPCs, responses to injury with the goal of finding novel therapeutics that can promote neuroprotection and repair; all within the context of the disease Multiple Sclerosis. Multiple Sclerosis can be a debilitating disease of the central nervous system in which components of the body’s immune system specifically target oligodendrocytes within the brain, spinal cord and optic nerves of the eyes. The function of an oligodendrocyte is to make and form tight insulation wraps, called myelin, around nerve cells. This enables nerve cells to transmit fast electrical signals and it also protects the nerve cell and provides support. Following loss of myelin and the oligodendrocyte the nerve cell cannot function correctly and ultimately degenerates resulting in the accrual of disability. For my research I utilize a range of techniques and tools centered around demyelination to study how endogenous OPCs migrate and differentiate in response to injury, how Multiple Sclerosis drug therapies and novel pathways, such as the renin-angiotensin system, interact with these cells, and identify novels targets to reduce or prevent oligodendrocyte loss and promote repair.
Digital fluorescence image of OPCs in culture(green NG2 and blue DAPI staining)
Digital fluorescence image of OPCs in culture(green NG2 and blue DAPI staining)