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From computational biology to new zebrafish and mouse models for Motor Neuron Disease, Parkinson’s and Multiple Sclerosis to structural neuroimaging studies in stroke and Alzheimer’s disease, the annual Department of Neuroscience research day held at SITraN on 16th October 2015 covered a vast range of topics and scientific approaches to neurodegenerative diseases.
Following a warm welcome by Head of Department, Professor Paul Ince, 43 postgraduate students and post-doctoral researchers presented their research during the day to their colleagues across the department in either a 15 minute talk, a 5-10 minute oral poster presentation or in the intermittent poster sessions. Highlights of the day were the presentations of EU Marie Curie Fellow Dr Luisa Cutillo on “Count data analysis and biological networks” and Parkinson’s UK Research Fellow Dr Heather Mortiboys on “Drug repurposing for Parkinson’s disease”.
Prizes for the best presentations went to PhD students Simeon Mihaylov who presented his research on the role of PGC1-alpha in energy homeostasis and Jodie Stephenson who presented her studies on a TDP43 mouse model of MND. The prize for the best oral poster presentation went to PhD student Natalie Rounding who talked about her research on the C9orf72 MND zebrafish model. Poster prizes went to Hannah Clemmens, Emma Smith and Khlood Mehdar.
A new study on motor neuron disease (MND) puts star-shaped helper cells in the brain, called astrocytes, in the spotlight. Researchers at the Sheffield Institute for Translational Neuroscience (SITraN) have revealed the full extent of astrocyte behaviour in a mouse model of MND from pre-symptomatic to late stages of the disease. Their findings suggest that astrocytes progressively lose the ability to support motor neurons as MND progresses which leads to the death of these specialised nerve cells that control our movements.
Co-lead of the study, Dr Janine Kirby, Senior Lecturer in Neurogenetics at the University of Sheffield, said: “Overall, our data suggest that astrocytes react to disease by engaging damage limitation strategies including clearing debris and waste from the motor neurons and redistributing components such as cholesterol, which is crucial for nerve cell function. However, as the disease progresses, astrocytes lose their supportive functions and the ability to control their external environment which ultimately leads to the death of the motor neurons.”
Astrocytes are key players in the progression of MND and other neurodegenerative diseases such as Alzheimer’s disease. They have many important supportive functions and are critical for the proper functioning and survival of nerve cells. In order to provide the first detailed map of astrocyte behaviour throughout the disease course, researcher and study co-author Dr David Baker investigated differences in gene expression in astrocytes in a well-characterised mouse model of MND which carries the SOD1G93A mutation. The team confirmed their findings with further enzymatic essays and in vitro experiments.
One of the senior researchers of this study, Marie Curie Research Fellow Dr Laura Ferraiuolo and the team at SITraN have previously shown that astrocytes at the pre-symptomatic stage are known to lose some supportive functions to motor neurons seen in the decreased provision of growth factors as well as lactate needed to generate energy. The new data show that as the disease progresses and symptoms occur, SOD1 astrocytes transition into an activated state. The reactive astrocytes show an altered stress and immune response compared to their healthy counterparts. Waste processing and recycling is increased through the activation of lysosomal and phagocytic pathways, most likely to protect nerve cells from the accumulation of cell debris which can cause inflammation and lead to cell death (apoptosis). The late stage shows additional changes in cholesterol production and distribution which is also critical for neuron survival.
Clinician Scientist in Neurology and MND specialist Professor Dame Pam Shaw, Director of SITraN and co-lead of this study, said: “Taken together, SOD1G93A astrocytes are characterized by a loss of supportive function towards motor neurons, as well as acquiring toxic properties during the disease course, and these factors in the neighbourhood of motor neurons compromise the health and survival of the nerve cells. The next step will be to determine whether astrocyte behaviour can be modulated or even restored, and whether this is a means by which to slow down disease progression in MND.”
Baker, DJ; Blackburn, DJ; Keatinge, M; Sokhi, D; Viskaitis, P; Heath, PR; Ferraiuolo, L; Kirby, J and Shaw, PJ (2015) Lysosomal and phagocytic activity is increased in astrocytes during disease progression in the SOD1G93A mouse model of amyotrophic lateral sclerosis. Front. Cell. Neurosc. 9:410. doi:10.3389/fncel.2015.00410
Scientists from the Sheffield Institute for Translational Neuroscience have joined a £1.3 million research initiative to find effective treatments for Spinal Muscular Atrophy (SMA), the leading genetic cause of death in babies and toddlers. The new UK research consortium, led and funded by the SMA Trust, is the first of its kind to investigate the childhood form of Motor Neuron Disease (MND).
SMA is a debilitating disease caused by a faulty gene that affects nerve cells needed to control the muscles we use for moving, swallowing and breathing. One in 40 people are a carrier for the disease and in the most severe cases, approximately half of those affected, children rarely live beyond two years. The consortium, announced today (Tuesday 29 September 2015) during the first ever UK SMA Awareness Week, consists of world-class research and clinical experts based at the University of Sheffield’s Institute for Translational Neuroscience (SITraN) as well as Oxford, Edinburgh and London universities.
The main aims of the project are to further develop existing drug targets and identify new neuroprotective therapies to maintain function throughout the lives of people living with SMA and to identify improved ways of delivering treatments in order to maximise benefit throughout the body.
Professor Mimoun Azzouz who leads an extensive research programme on SMA at SITraN said: "This is a great initiative for SMA research in the UK. Significant progress has been made in the field, however the creation of this consortium will bring together excellent SMA experts to further our understanding of the disease and accelerate therapy development."
The SMA Trust has spent nearly £3 million since it was founded and now funds 75 per cent of all UK charity funded research into the condition. It also helped create SMA Europe, an umbrella organisation that funds research projects all over Europe and the US, as well as promoting knowledge-sharing, collaboration and representation of a united ‘patient voice’ to pharmaceutical companies and regulatory authorities involved in clinical trials.
Joanna Mitchell, CEO of The SMA Trust said: “These are exciting times in SMA research and for the new UK research consortium. Recent years have seen rapid advances, with several companies now actively pursuing clinical trials for potential treatments. Whilst a cure for SMA remains the ultimate goal, we also recognise that, for the time being, ‘success’ is equally likely to come in the form of combinations of treatments that improve the quality of life of people living with SMA.”
The potential therapies for SMA currently in clinical trials are mainly concerned with increasing the amount of a crucial protein called Survival Motor Neuron (SMN), which is depleted in various degrees in people who have SMA. This offers great promise for treating SMA if such therapies can be delivered before motor neuron loss is established. However, it is believed that the principal effect of the SMN protein on the neuromuscular system occurs early in development, meaning that increasing the levels of SMN after development has occurred may not result in a substantial benefit on motor function for the majority of people living with SMA. This becomes an increasingly important issue as due to advances in therapies which increase SMN levels, more people will be living into adulthood with SMA in the future.
The Consortium, led by Professor Kevin Talbot at Oxford University, will seek to address this problem by looking more closely at the specific mechanisms of neuromuscular failure in the disease and investigating whether influencing other ‘non-SMN’ pathways will identify potential therapies which will benefit all individuals living with SMA by maintaining and enhancing the function of surviving motor neurons.
Listen to Prof Mimoun Azzouz talking about the new UK SMA research consortium on BBC Radio Sheffield live on 29th September with Howard Pressmann. The interview starts at 01:36:50.
More than 40 researchers from across departments of The University of Sheffield and Sheffield Hallam University met on 22 September at SITraN to exchange their knowledge on glia and the role of these cells in neurological diseases. The networking event was sponsored by the Biochemical Society and brought together scientists working on a wide range of topics and approaches.
Highlights of the day: Alzheimer’s Society Research Fellow Dr Claire Garwood from SITraN reported on how impaired insulin signalling in human astrocytes is thought to contribute to dementia pointing to interesting links between diabetes and Alzheimer’s disease; Professor Matthew Holley from the Department of Biomedical Sciences presented findings from transplantation studies where glial scar tissue seems to serve as a guide for nerve cells to reach their destination; Dr Leandro Beltrachini from the Department of Electric and Electrical Engineering talked about how diffusion MRI can be used to generate in silico white matter models.
The meeting closed with a fantastic plenary talk by Professor Alexej Verkhratsky from the University of Manchester giving a comprehensive overview on the history of glia research and state of current knowledge, dispelling common myths and misconceptions.
The organisers Dr Claire Garwood from SITraN and Dr Clare Howarth from the Department of Psychology said: “Glia play a central role in neurological diseases and it is great to see that an increasing number of scientists are looking at these brain cells which seem to play a crucial role in protecting our nerve cells from damage and ultimately from diseases like Alzheimer’s disease and Motor Neurone Disease.”
A drug which has already been in use for decades to treat liver disease could be an effective treatment to slow down progression of Parkinson’s disease, scientists from the University of Sheffield have discovered.
The research led by academics from the Sheffield Institute for Translational Neuroscience (SITraN), in collaboration with scientists from the University of York, supports the fast-tracking of the drug ursodeoxycholic acid (UDCA) for a clinical trial in Parkinson’s patients.