Dr Scott Allen

PhD

Neuroscience, School of Medicine and Population Health

Lecturer in Neuroscience

s.p.allen@sheffield.ac.uk
+44 114 215 9103

+44 114 222 2290 (fax)

Sheffield Institute for Translational Neuroscience (SITraN)

Full contact details

Dr Scott Allen
Neuroscience, School of Medicine and Population Health
Sheffield Institute for Translational Neuroscience (SITraN)
385a Glossop Road
Sheffield
S10 2HQ

Profile

I obtained my PhD from the University of Manchester where I characterised protein import and folding in the mitochondrial intermembrane space. My work showed that juxta-positioned intradisulphide bonding through transfer of electrons to cytochrome c via Erv1, is key for the folding of the TIM proteins. My work was highlighted on the front cover of the Journal of Molecular Biology (Allen et al (2005). J. Mol. Biol. 353:937-44).

I followed this up with a post-doctoral position focussing on the myelin sheath proteolipid protein and its folding in the endoplasmic reticulum. I then moved into the pharmaceutical industry with AstraZeneca developing biochemical assays to validate RNA aptamers as small molecule inhibitors and lentiviral vectors as shRNA delivery tools.

I joined the Division of Neuroscience at the University of Sheffield in 2009. I was the first in the field to use an XF bioanalyser (Seahorse Bioscience) to simultaneously measure the effect of MND on mitochondrial and glycolytic function in disease cellular models. Using this technology, we discovered in 2013 that oxidative stress is not only detrimental to mitochondrial function but also glycolytic function in cell models overexpressing mutant forms of the SOD1 protein.

In 2014, we showed that skin cells isolated from MND patients show similar mitochondrial dysfunction to that observed in the CNS. However, unlike in the CNS, the skin cells can upregulate their glycolytic pathways to maintain energy levels. Through transcriptomics and functional analysis, we found that there are significant changes in key metabolic regulators and altered metabolic function in skin cells isolated from sporadic cases and that these sporadic cases have an altered metabolic response to aging compared to controls.

Recently, I was the first in the field to use a phenotypic metabolic profiling system (OmniLog™) to screen MND patient cell lines. This approach in combination with metabolic flux analysis has identified a number of novel targets for MND study.

Qualifications

Fellow of the Higher Education Academy

2016-2019
Motor Neurone Disease Association Senior, Non-Clinical Fellow
Sheffield Institute for Translational Neuroscience, the University of Sheffield

2009-2015
Senior Post-Doctoral Researcher
Sheffield Institute for Translational Neuroscience, the University of Sheffield

2006-2008
Post-Doctoral Researcher
AstraZeneca

2004-2006
Post-Doctoral Research Associate
The University of Manchester, Faculty of Life Sciences

2000-2004
PhD The University of Manchester
Faculty of Life Sciences

Research interests

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). Our primary aim is to develop therapeutic strategies by:

Using phenotypic metabolic screening to identify novel targets for therapeutic intervention using patient-derived fibroblasts and induced neural progenitor cell derived human astrocytes and neurones.
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 main research tools and techniques used in my laboratory are:

Human iNPC astrocytes and neurones derived from fibroblasts through direct reprogramming (collaboration with Prof Laura Ferraiuolo and Prof Heather Mortiboys).
Mouse stem cells expressing the green fluorescent protein under the Hb9 promoter, resulting. in GFP+ motor neurons (collaboration with Prof Laura Ferraiuolo, University of Sheffield using cells kindly donated by Professor Thomas Jessell (Howard Hughes Medical Institute).
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 motor neurone disease 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 role of ALS/MND in glycosylation. In collaboration with Dr Ryan West and Dr Caroline Evans. Seeking funding, including externally funded PhD students.
How fructose metabolism affects energy generation in MND astrocytes. Seeking funding, including externally funded PhD students.
The effect of DPRs on carbon flow in C9orf72-ALS. Currently seeking external funding.
The effect of aging and C9orf72 expansion on the astrocyte response to hypoxia. Currently seeking external funding.

Publications

Journal articles

Roscoe S, Skinner E, Kabucho Kibirige E, Childs C, Weekes CE, Wootton S, Allen S, McDermott C & Stavroulakis T (2023) 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.
Hall B, George JG & Allen SP (2021) Adenosine deaminase, not immune to a mechanistic rethink in central nervous system disorders?. Histol Histopathol, 18404.
Gerou M, Hall B, Woof R, Allsop J, Kolb SJ, Meyer K, Shaw PJ & Allen SP (2021) Amyotrophic lateral sclerosis alters the metabolic aging profile in patient derived fibroblasts. Neurobiology of Aging.
Allen SP, Seehra RS, Heath PR, Hall BPC, Bates J, Garwood CJ, Matuszyk MM, Wharton SB & Simpson JE (2020) 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
Floare M-L & Allen SP (2020) Why TDP-43? Why not? Mechanisms of metabolic dysfunction in amyotrophic lateral sclerosis. Neuroscience Insights, 15.
Lee JAK, Hall B, Allsop J, Alqarni R & Allen SP (2020) Lipid metabolism in astrocytic structure and function. Seminars in Cell & Developmental Biology. View this article in WRRO
Allen S (2020) 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
Allen SP, Hall B, Woof R, Francis L, Gatto N, Shaw AC, Myszczynska M, Hemingway J, Coldicott I, Willcock A , Job L et al (2019) C9orf72 expansion within astrocytes reduces metabolic flexibility in amyotrophic lateral sclerosis. Brain, 1-20. View this article in WRRO
Stopford M, Allen S & Ferraiuolo L (2019) 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
Allen S, Hall B, Castelli L, Frances L, Woof R, Siskos A, Kouloura E, Gray E, Thompson A, Talbot K , Higginbottom A et al (2019) Astrocyte adenosine deaminase loss increases motor neuron toxicity in amyotrophic lateral sclerosis. Brain, 142(3), 586-605. View this article in WRRO
Feng S, Bowden N, Fragiadaki M, Souilhol C, Hsiao S, Mahmoud M, Allen S, Pirri D, Ayllon BT, Akhtar S , Thompson AAR et al (2017) 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
Allen SP, Duffy LM, Shaw PJ & Grierson AJ (2015) 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
Raman R, Allen SP, Goodall EF, Kramer S, Ponger L-L, Heath PR, Milo M, Hollinger HC, Walsh T, Highley JR , Olpin S et al (2015) 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
Allen SP, Rajan S, Duffy L, Mortiboys H, Higginbottom A, Grierson AJ & Shaw PJ (2014) 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.
Richardson K, Allen SP, Mortiboys HJ, Grierson AJ, Wharton SB, Ince PG, Shaw PJ & Heath PR (2013) 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
Mead RJ, Higginbottom A, Allen SP, Kirby J, Bennett E, Barber SC, Heath PR, Coluccia A, Patel N, Gardner I , Brancale A et al (2013) 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.
Allen S, Balabanidou V, Sideris DP, Lisowsky T & Tokatlidis K (2005) 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.
Lu H, Allen S, Wardleworth L, Savory P & Tokatlidis K (2004) Functional TIM10 Chaperone Assembly Is Redox-regulatedin Vivo. Journal of Biological Chemistry, 279(18), 18952-18958.
Lu H, Golovanov AP, Alcock F, Grossmann JG, Allen S, Lian L-Y & Tokatlidis K (2004) The Structural Basis of the TIM10 Chaperone Assembly. Journal of Biological Chemistry, 279(18), 18959-18966.
Allen S, Lu H, Thornton D & Tokatlidis K (2003) 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.
Vial S, Lu H, Allen S, Savory P, Thornton D, Sheehan J & Tokatlidis K (2002) Assembly of Tim9 and Tim10 into a Functional Chaperone. Journal of Biological Chemistry, 277(39), 36100-36108.
Allen SP, Al Sultan A, Kabucho Kibirige E, Tonkiss E, Hamer KJ, Castelli LM, Lin Y-H, Roscoe S, Stefanidis N, Mead RJ , Highley JR et al () 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.
Cooper‐Knock J, Julian TH, Feneberg E, Highley JR, Sidra M, Turner MR, Talbot K, Ansorge O, Allen SP, Moll T , Shelkovnikova T et al () Atypical TDP ‐43 protein expression in an ALS pedigree carrying a p. Y374X truncation mutation in TARDBP. Brain Pathology.
Boddy S, Islam M, Moll T, Kurz J, Burrows D, McGown A, Bhargava A, Julian TH, Harvey C, Marshall JNG , Hall BPC et al () Unbiased metabolome screen leads to personalised medicine strategy for amyotrophic lateral sclerosis. Brain Communications.
Bell SM, Burgess T, Lee J, Blackburn DJ, Allen SP & Mortiboys H () Peripheral Glycolysis in Neurodegenerative Diseases. International Journal of Molecular Sciences, 21(23), 8924-8924.

Conference proceedings papers

Allen SP, Hall B, Castelli L, Francis L, Woof R, Higginbottom A, Myszczynska M, Allen CF, Stopford MJ, Webster CP , De Vos K et al (2018) 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

Pirri D, Tian S, Tardajos-Ayllon B, Irving S, Donati F, Allen SP, Mammoto T, Vilahur G, Miller C, Schenkel T , Chambers EV et al (2023) EPAS1 Attenuates Atherosclerosis Initiation at Disturbed Flow Sites through Endothelial Fatty Acid Uptake, Cold Spring Harbor Laboratory.
Roscoe S, Skinner E, Kibirige EK, Childs C, Weekes CE, Wootton S, Allen S, McDermott C & Stavroulakis T (2022) A critical view of the use of predictive energy equations for the identification of hypermetabolism in motor neuron disease, Cold Spring Harbor Laboratory.

Grants

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: 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, Translational Pathology and Molecular Medicine focussing on metabolomics. I have supervised 19 MSc students, 6, PhD students, (as well as 6 technicians and 2 post-doctoral researcher) and numerous undergraduate students. I am a ECR Departmental Champion and ECR prize committee Chair, an MSc mentor and a Personal Academic Tutor for medical students.

Professional activities and memberships

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)
Trustee of the Nick Smith Foundation
Director of the Readable Research lay summary initiative

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

School of Medicine and Population Health