Dr Scott Allen
PhD
School of Medicine and Population Health
Senior Lecturer in Neuroscience
s.p.allen@sheffield.ac.uk
+44 114 215 9103
+44 114 215 9103
Sheffield Institute for Translational Neuroscience (SITraN)
Full contact details
Dr Scott Allen
School of Medicine and Population Health
Sheffield Institute for Translational Neuroscience (SITraN)
385a Glossop Road
Sheffield
S10 2HQ
School of Medicine and Population Health
Sheffield Institute for Translational Neuroscience (SITraN)
385a Glossop Road
Sheffield
S10 2HQ
- Profile
-
I am an established researcher in the field of metabolic dysfunction in neurodegenerative diseases with a strong mechanistic and translational focus. My research focuses on using emerging technologies to understand mechanisms of metabolic dysfunction that occur in the CNS. My long-term goals are to use this understanding to develop gene therapy, small molecule, and nutritional strategies to slow down progression in diseases such as motor neurone disease. My work bridges the gap between bench science and clinical science directly, with projects combining both fields of translational neuroscience. My current main research projects are.
- Using patient derived cell models to understand how defects in purine metabolism result in loss of astrocyte support for motor neurones and whether that can be corrected by gene therapy.
- Identifying mechanisms of glycolytic dysfunction in MND and identifying small molecules that ameliorate the dysfunction.
- Identifying the nutritional needs of people with MND by identifying metabolic signatures in patient biofluids.
- Combining in vivo fly modelling with patient derived cell models to understand the role of hypoxia in MND/FTD.
- Assessing the effect of aging and C9orf72-HREs on metabolic function and the response to hypoxia, combined with metabolic biomarker identification in blood.
- Qualifications
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Fellow of the Higher Education Academy
2016-2019
Motor Neurone Disease Association Senior, Non-Clinical Fellow
Sheffield Institute for Translational Neuroscience, the University of Sheffield2009-2015
Senior Post-Doctoral Researcher
Sheffield Institute for Translational Neuroscience, the University of Sheffield2006-2008
Post-Doctoral Researcher
AstraZeneca2004-2006
Post-Doctoral Research Associate
The University of Manchester, Faculty of Life Sciences2000-2004
PhD The University of Manchester
Faculty of Life Sciences
- Research interests
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The main research focus of my group is identifying the role of dysfunctional energy generation in neurodegenerative conditions, with particular interest in Motor Neurone Disease (MND) and dementia. Our primary aim is to develop therapeutic strategies by:
- Using phenotypic metabolic screening to identify novel targets for therapeutic intervention using patient-derived fibroblasts, induced neural progenitor cell derived human astrocytes/neurones and PBMCs
- Using fly models of MND and dementia to understand disease mechanisms in vivo
- Develop nutritional supplementation regimes for people with MND.
In vitro we use various cell models, including primary patient cells and genetically reprogrammed human progenitor cells and in vivo we use models such as Drosophila Melanogaster to investigate the role of astrocyte and neurone energy metabolism and how they affect disease progression. We are specifically interested in;
- How astrocyte purine pathway dysfunction effects pathogenesis in CNS disorders such as MND and MS.
- How metabolism responds to disease specific cellular stress such as hypoxia.
- How MND affects the metabolic response to ageing in astrocytes
- How nutritional status analysis can inform patient care in MND (collaboration with Dr Haris Stavroulakis and Professor Christopher McDermott).
- How disrupted glycolysis effects the cellular antioxidant response via MGO (collaboration with Dr Richard Mead)
- How oxygen glucose deprivation affects mitochondrial function (collaboration with Professor Arshad Majid)
- How glycosylation is altered in MND.
- Analysis of MND pathogenic mechanisms in Drosophila Melanogaster (collaboration with Dr Ryan West).
- Metabolomic analysis to assess metabolic substrate levels in iNPC astrocytes (collaboration with Prof Hector Keun, ICL and Dr Heather Walker UoS).
- The role of artificial sweeteners in MND disease pathogenesis
The main research tools and techniques used in my laboratory are:
- Human iNPC astrocytes and neurones derived from fibroblasts through direct reprogramming
- PBMCs, serum, plasma and urine from people with MND (collaboration with Dr Theocharis Stavroulakis and Prof Christopher McDermott).
- Mouse cortical neurones
- Metabolic screening using an OmniLog™ metabolic profiling system.
- Metabolic flux analysis using an XF96 bioanalyser.
Current Projects
- The role of adenosine deaminase in MND- Funded by the MND Association.
- Investigating how the MGO-NRF2 cellular protection pathway is affected in MND. In collaboration with Prof Hector Keun (Imperial College London) and Dr Richard Mead. Funded by the Academy of Medical Sciences, the Motor Neurone Disease Association and Faculty of Health PhD Scholarship.
- Investigating nutritional status in MND. Collaboration with Dr Theocharis Stavroulakis and Prof Christopher McDermott. Funded by the NIHR, the Darby Rimmer Foundation and the Sheffield BRC and the Motor Neurone Disease Association
- Investigating the effect of C9orf72 on mitochondrial neuronal function. Collaboration with Prof Heather Mortiboys. Funded by the Battelle Association and the MND Association.
- How hypoxia affects metabolic energy generation in MND in collaboration with Dr Ryan West. Funded by the MND Association
- The link between Neat1 and glycolysis. In collaboration with Dr Tatyana Shelkovnikova. Funded by the MND Association.
- The effect of aging and C9orf72 expansion on carbon flow under normoxia and hypoxia in C9orf72-ALS. Funded by the MND Association, in collaboration with Dr Ryan West and Prof Dame Pamela Shaw
- How fructose metabolism affects energy generation in MND astrocytes and neurones. Seeking funding, including externally funded PhD students.
- How polyol metabolism affects astrocytes and neuronal function with age in sporadic MND. Seeking funding, including externally funded PhD students.
- Publications
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Journal articles
- EPAS1 Attenuates Atherosclerosis Initiation at Disturbed Flow Sites Through Endothelial Fatty Acid Uptake.. Circ Res.
- Activation of the Keap1/Nrf2 pathway suppresses mitochondrial dysfunction, oxidative stress, and motor phenotypes inC9orf72ALS/FTD models. Life Science Alliance, 7(9), e202402853-e202402853.
- A critical view of the use of predictive energy equations for the identification of hypermetabolism in motor neuron disease: a pilot study. Clinical Nutrition ESPEN.
- Adenosine deaminase, not immune to a mechanistic rethink in central nervous system disorders?. Histol Histopathol, 18404.
- Amyotrophic lateral sclerosis alters the metabolic aging profile in patient derived fibroblasts. Neurobiology of Aging.
- Transcriptomic analysis of human astrocytes in vitro reveals hypoxia-induced mitochondrial dysfunction, modulation of metabolism, and dysregulation of the immune response. International Journal of Molecular Sciences, 21(21). View this article in WRRO
- Why TDP-43? Why not? Mechanisms of metabolic dysfunction in amyotrophic lateral sclerosis. Neuroscience Insights, 15.
- Lipid metabolism in astrocytic structure and function. Seminars in Cell & Developmental Biology. View this article in WRRO
- Understanding metabolic flexibility : a potential key to unlocking metabolic therapies in amyotrophic lateral sclerosis?. Neural Regeneration Research, 15(9), 1654-1654. View this article in WRRO
- C9orf72 expansion within astrocytes reduces metabolic flexibility in amyotrophic lateral sclerosis. Brain, 1-20. View this article in WRRO
- A high-throughput and pathophysiologically relevant astrocyte-motor neuron co-culture assay for amyotrophic lateral sclerosis therapeutic discovery. Bio-protocol, 9(17). View this article in WRRO
- Astrocyte adenosine deaminase loss increases motor neuron toxicity in amyotrophic lateral sclerosis. Brain, 142(3), 586-605. View this article in WRRO
- Mechanical Activation of Hypoxia-Inducible Factor 1α Drives Endothelial Dysfunction at Atheroprone Sites.. Arteriosclerosis, Thrombosis, and Vascular Biology, 37(11), 2087-2101. View this article in WRRO
- Altered age-related changes in bioenergetic properties and mitochondrial morphology in fibroblasts from sporadic amyotrophic lateral sclerosis patients. Neurobiology of Aging, 36(10), 2893-2903. View this article in WRRO
- Gene expression signatures in motor neurone disease fibroblasts reveal dysregulation of metabolism, hypoxia-response and RNA processing functions. Neuropathology and Applied Neurobiology, 41(2), 201-226. View this article in WRRO
- Superoxide dismutase 1 mutation in a cellular model of amyotrophic lateral sclerosis shifts energy generation from oxidative phosphorylation to glycolysis.. Neurobiol Aging, 35(6), 1499-1509.
- The Effect of SOD1 Mutation on Cellular Bioenergetic Profile and Viability in Response to Oxidative Stress and Influence of Mutation-Type.. Plos One, 6(8), e68256-e68256. View this article in WRRO
- S[+] Apomorphine is a CNS penetrating activator of the Nrf2-ARE pathway with activity in mouse and patient fibroblast models of amyotrophic lateral sclerosis.. Free Radic Biol Med, 61, 438-452.
- Erv1 Mediates the Mia40-dependent Protein Import Pathway and Provides a Functional Link to the Respiratory Chain by Shuttling Electrons to Cytochrome c. Journal of Molecular Biology, 353(5), 937-944.
- Functional TIM10 Chaperone Assembly Is Redox-regulatedin Vivo. Journal of Biological Chemistry, 279(18), 18952-18958.
- The Structural Basis of the TIM10 Chaperone Assembly. Journal of Biological Chemistry, 279(18), 18959-18966.
- Juxtaposition of the Two Distal CX3C Motifs via Intrachain Disulfide Bonding Is Essential for the Folding of Tim10. Journal of Biological Chemistry, 278(40), 38505-38513.
- Assembly of Tim9 and Tim10 into a Functional Chaperone. Journal of Biological Chemistry, 277(39), 36100-36108.
- Exploring the role of anthropometric measurements to assess nutritional status in amyotrophic lateral sclerosis: a longitudinal prospective cohort study. Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration, 1-14.
- Mapping the Evidence for Measuring Energy Expenditure and Indicating Hypermetabolism in Motor Neuron Disease: A Scoping Review. Nutrition Reviews.
- A Y374X TDP43 truncation leads to an altered metabolic profile in amyotrophic lateral sclerosis fibroblasts driven by pyruvate and TCA cycle intermediate alterations. Frontiers in Aging Neuroscience, 15, 1151848-1151848.
- Atypical
TDP ‐43 protein expression in anALS pedigree carrying a p.Y374X truncation mutation in TARDBP. Brain Pathology.
- Unbiased metabolome screen leads to personalised medicine strategy for amyotrophic lateral sclerosis. Brain Communications.
- Peripheral Glycolysis in Neurodegenerative Diseases. International Journal of Molecular Sciences, 21(23), 8924-8924.
Chapters
- From use of omics to systems biology: Identifying therapeutic targets for amyotrophic lateral sclerosis, International Review of Neurobiology (pp. 209-268). Elsevier
Conference proceedings papers
- Inosine reverses motor neuron toxicity observed in amyotrophic lateral sclerosis patient astrocytes with an adenosine deaminase deficiency. Biochimica et Biophysica Acta (BBA) - Bioenergetics, Vol. 1859 (pp e23-e23)
Preprints
- C9orf72-ALS mutation drives mitophagy impairments in iNeurons, Cold Spring Harbor Laboratory.
- EPAS1 Attenuates Atherosclerosis Initiation at Disturbed Flow Sites through Endothelial Fatty Acid Uptake, Cold Spring Harbor Laboratory.
- A critical view of the use of predictive energy equations for the identification of hypermetabolism in motor neuron disease, Cold Spring Harbor Laboratory.
- EPAS1 Attenuates Atherosclerosis Initiation at Disturbed Flow Sites Through Endothelial Fatty Acid Uptake.. Circ Res.
- Grants
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- 2022- MNDA Association, £278,500. Investigating the role of adenosine deaminase in ALS.
- 2021- Progressive MS Alliance, 75,000 Euros. Investigating adenosine signalling in MS.
- 2021- Darby Rimmer Foundation, £34,372. Understanding Nutrition in MND.
- 2021- Battelle PhD + MND Association, £95,000. Mitochondrial phenotyping in MND.
- 2020- Academy of Medical Sciences, £99997. Investigating the MGO-NRF2 pathway in MND.
- 2018- Alzheimer’s Research UK, £98,594.70. Equipment grant application for an i2/H35 Hypoxic Chamber PI, Scott Allen
- 2016- Neurocare Charitable Trust £72,000. Equipment proposal for an OmniLog™ system. PI, Scott Allen
- 2015- The Motor Neurone Disease Association-£248,000. Senior Non-Clinical Fellowship
- 2014-Neurocare Charitable Trust-£5600. Metabolic Profiling Pilot Study funding
- 2010- Neurocare Charitable Trust £71,967. Equipment proposal for Seahorse XF24 Bioanalyser. PI, Scott Allen
Our Funders
- The Motor Neurone Disease Association (MNDA)
- Neurocare
- Alzheimer's Research UK
- MS Alliance
- Darby Rimmer Foundation
- Sheffield BRC
- Battelle Association
- Teaching activities
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I co-lead the Ethics in Neuroscience MSc module for the Department. I teach on the MSc courses in Advanced Therapies, Clinical Neuroscience, Translational Neuroscience, and Molecular Medicine focussing on metabolomics. I have supervised 22 MSc students, 7 PhD students, (as well as 6 technicians and 3 post-doctoral researcher) and numerous undergraduate students. I am a ECR Departmental Lead and ECR prize committee Chair, an MSc mentor and a Personal Academic Tutor for medical students.
- Professional activities and memberships
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- Member of the Royal Society International Exchange Grant Panel
- Reviewer for several funding bodies, including the Motor Neurone Disease Association (MNDA), the Medical Research Council (MRC), the British Biotechnology Scientific Research Council (BBSRC), Action for A-T
- Reviewer for several Journals including Brain Communications, Molecular Neurobiology, Cell Regeneration, Journal of Neurology, Neurosurgery, and Psychiatry amongst others. Editorial Board Member of Archives of Neurology and Neuro Disorders
- Scientific link on the Sheffield Motor Neurone Disorder Research Advisory Group (SMND-RAG)
- External Examiner for the University of Hull MSc in Biomedical Sciences course
- REF-UoA4 Neuroscience Lead for the SMPH
- KE Champion for Neuroscience
- Awards
2023
- Faculty PhD Scholarship Investigating the link between metabolism, MGO and Nrf-2 ~£84,000
- MND Association- PhD Consumables Funding Investigating the link between metabolism, MGO and Nrf-2 £27,000.
- MND Association PhD projects Neat1 in ALS in ALS ~£114,917(CO-PI) 50%
- MND Association PhD project-Hypoxia in ALS ~£114,917 (CO-PI) 50%
- MND Association Small grant funding Developing Nutritional Strategies in ALS £43,000 (CO-PI-30%).
- Departmental Funding. Developing a Brand for the Lay summary scheme £4500
- BRC Funding Developing a Brand for the Lay summary scheme £4500.
- BRC Funding Wet Biomarker Development £146,000 (CO-PI)
2022
- MND Association, £278,500. Investigating the role of adenosine deaminase in ALS.
2021
- Progressive MS Alliance, 75,000 Euros. Investigating adenosine signalling in MS.
- Darby Rimmer Foundation, £34,372. Understanding Nutrition in MND.
- Battelle PhD + MND Association, £95,000. Mitochondrial phenotyping in MND.
2020
- Academy of Medical Sciences, £99997. Investigating the MGO-NRF2 pathway in MND.
2018
- Alzheimer’s Research UK, £98,594.70. Equipment grant application for an i2/H35 Hypoxic Chamber PI, Scott Allen
2016
- Neurocare Charitable Trust £72,000. Equipment proposal for an OmniLog™ system. PI, Scott Allen
2015
- The Motor Neurone Disease Association-£248,000. Senior Non-Clinical Fellowship
2014
- Neurocare Charitable Trust-£5600. Metabolic Profiling Pilot Study funding
2010
- Neurocare Charitable Trust £71,967. Equipment proposal for Seahorse XF24 Bioanalyser. PI, Scott Allen
Our Funders
The Motor Neurone Disease Association (MNDA)
Academy of Medical Sciences
Neurocare
Alzheimer's Research UK
MS Alliance