While some of the Plymouth Institute of Health and Care Research's neuroscience work is disease-orientated (brain and mind translation research), our discovery research seeks to understand the pathological processes that give rise to neurodegenerative diseases (such as Multiple Sclerosis, Alzheimer's, Motor Neurone and Parkinson's diseases) as well as disorders of myelinating cells, ischemia and brain tumours. This research is supported by the core investigation of fundamental mechanisms, such as cell death and regeneration
Damage repair and network formation in the Central Nervous System
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. We are 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 we study the embryonic development of the CNS to understand how damage to it can be repaired. We also investigate the transcriptional program that ensures the correct formation of neural networks controlling movement.
Development, repair and tumour formation in the Peripheral Nervous System
Our 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.
Guiding regenerating axons across peripheral nerve gaps
This research focuses on studying how developmental axon guidance cues control adult peripheral nerve regeneration. Peripheral nerve transection injury following trauma often generates a nerve gap between the proximal and distal nerve stumps, which prevents correct re-targeting of regenerating axons into the distal nerve. Consequently, effective repair following peripheral nerve transection remains a significant challenge in order to achieve precise axon re-targeting into the distal nerve stump and regain full nerve function following such an injury. We aim to understand their molecular and cellular mechanisms in peripheral nerve regeneration and then develop novel therapeutic strategies to guide regenerating axons across peripheral nerve gaps.
Dr Xinpeng Dun
Our research investigates autophagy regulation and its roles in Huntington's Disease and other neurodegenerative diseases. 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.
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.
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’s.
Neural Stem Cell (De)regulation and Brain Tumour Initiation
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 or their lineage can lead to a variety of brain disorders, including tumour formation. Our team uses one of the best in vivo genetic models available, the Drosophila central nervous system, to reveal signals controlling Neural Stem Cell mitotic activation, cell fate and lineage maturation in both normal and pathological conditions such as upon brain tumour initiation and growth.
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.
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.