Dr Scott Allen PhD
Motor Neurone Disease Association, Senior Non-Clinical Fellow, University of Sheffield
Department of Neuroscience
University of Sheffield
385a Glossop Road
Telephone: +44 (0) 114 2159103
Fax: +44 (0)114 22 22290
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 Department 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.
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:
1. Using phenotypic metabolic screening to identify novel targets for therapeutic intervention using patient-derived fibroblasts and induced neuronal progenitor cell derived human astrocytes.
2. 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 zebrafish to investigate the role of astrocyte and neurone energy metabolism and how they affect disease progression. We are interested in;
1. How MND effects metabolic pathway regulation and interaction.
2. How metabolism responds to disease specific cellular stress such as oxidative stress and hypoxia.
3. How the disease affects the metabolic response to aging in patients.
The main research tools and techniques used in my laboratory are:
1. Human astrocytes and neurons derived from fibroblasts through genetic reprogramming (collaboration with Dr Laura Ferraiuolo, (University of Sheffield)).
2. Mouse stem cells expressing the green fluorescent protein under the Hb9 promoter, resulting. in GFP+ motor neurons (collaboration with Dr Laura Ferraiuolo, University of Sheffield using cells kindly donated by Professor Thomas Jessell (Howard Hughes Medical Institute).
3. Metabolic screening using an OmniLog™ metabolic profiling system.
4. Metabolic flux analysis using an XF24 bioanalyser.
5. Analysis of neuronal stress in zebrafish models of MND
6. Hydrophobic interaction liquid chromatography-Mass spectrometry to assess nucleoside levels in patient Cerebrospinal fluid (CSF) (collaboration with Prof Martin Turner (University of Oxford) and Dr Hector Keun (Imperial College London).
Current projects which we are seeking both funding and PhD students for include (please contact me directly if interested (email@example.com);
1. The role of adenosine deaminase in MND.
2. How MND affects metabolic substrate transport.
3. How MND affects glycogen storage and mobilisation.
4. How fructose metabolism affects energy generation in MND astrocytes.
5. Investigating the protective role of estradiol in MND (collaboration with Dr Tennore Ramesh).
6. Metabolic screening of sporadic Parkinson’s disease patient fibroblasts and astrocytes (collaboration with Dr Heather Mortiboys and Prof Oliver Bandmann).
7. How hypoxia affects metabolic energy generation in Alzheimer’s disease and motor neurone disease (collaboration with Dr Julie Simpson and Dr Claire Garwood).
8. The role of inosine in MND (collaboration with Prof Martin Turner (Oxford) and Dr Hector Keun (Imperial College London).
9. How spinal muscular atrophy (SMA) affect energy pathway flux (collaboration with Dr Paul Heath).
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
The Motor Neurone Disease Association (MNDA)
Alzheimer's Research UK
Reviewer for several funding bodies, including the Motor Neurone Disease Association (MNDA) and the Medical Research Council (MRC).
Scientific link on the Sheffield Motor Neurone Disorder Research Advisory Group (SMND-RAG).
|Teaching Interests||I teach on the MSc courses in Translational Neuroscience, Translational Pathology and Molecular Medicine focussing on metabolomics. I also supervise MSc and undergraduate project placement students during their research projects.|
Astrocyte adenosine deaminase loss increases motor neuron toxicity in amyotrophic lateral sclerosis. Allen SP, Hall B, Castelli LM, Francis L, Woof R, Siskos AP, Kouloura E, Gray E, Thompson AG, Talbot K, Higginbottom A, Myszczynska M, Allen CF, Stopford MJ, Hemingway J, Bauer CS, Webster CP, De Vos KJ, Turner MR, Keun HC, Hautbergue GM, Ferraiuolo L, Shaw PJ. Brain. 2019 42:586-605.
Mechanical Activation of Hypoxia-Inducible Factor 1α Drives Endothelial Dysfunction at Atheroprone Sites Feng S, Bowden N, Fragiadaki M, Souilhol C, Hsiao S, Mahmoud M, Allen S, Pirri D, Ayllon BT, Akhtar S, Thompson AAR, Jo H, Weber C, Ridger V, Schober A & Evans PC (2017). Arterioscler Thromb Vasc Biol. 2017. 37: 2087-2101.
Altered age related changes in bioenergetic properties and mitochondrial morphology in fibroblast from sporadic amyotrophic lateral sclerosis (SALS). Allen SP, Duffy L, Shaw PJ, and Grierson AJ. Neurobiol. Aging. 2015. 36: 2893-903
Gene expression signatures in motor neurone disease fibroblasts reveal dysregulation of metabolism, hypoxia-response and RNA processing functions. Raman R and Allen SP, Goodall EF, Kramer S, Ponger LL, Heath PR, Milo M, Hollinger HC, Walsh T, Highley JR, Olpin S, McDermott CJ, Shaw PJ, Kirby J. Neuropathol. Appl. Neurobiol. 2015. 41:201-26
Superoxide dismutase 1 mutation in a cellular model of amyotrophic lateral sclerosis shifts energy generation from oxidative phosphorylation to glycolysis. Allen SP, Rajan S, Duffy L, Mortiboys H, Higginbottom A, Grierson AJ, Shaw PJ. Neurobiol. Aging. 2014. 35:1499-509.
The effect of SOD1 mutation on cellular bioenergetic profile and viability in response to oxidative stress and influence of mutation-type. Richardson K, and Allen SP, Mortiboys H, Grierson AJ, Wharton SB, Ince PG, Shaw PJ, Heath PR. PLoS One. 2013. 28:e68256.
S[+] Apomorphine is a CNS penetrating activator of the Nrf2-ARE pathway with activity in mouse and patient fibroblast models of amyotrophic lateral sclerosis. Mead RJ, Higginbottom A, Allen SP, Kirby J, Bennett E, Barber SC, Heath PR, Coluccia A, Patel N, Gardner I, Brancale A, Grierson AJ, Shaw PJ. Free Radic. Biol. Med. 2013. 61:438-52.