Sheffield Institute for
Translational Neuroscience

Motor Neurone Disease Association Senior Non-Clinical Fellow, University of Sheffield.


Research Interests

My main research focus is how motor neurone disease (MND) affects the major energy generation pathways in the central nervous system (CNS). 
Specifically;

  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 long term goals of this research are to identify metabolic biomarkers of disease, uncover therapeutic targets and develop energy supplementation regimes for MND patients.

Current Projects

Current ongoing projects include;

  1. Generating phenotypic metabolic profiles of patient-derived fibroblasts, induced neuronal progenitor cell derived human astrocytes and cortical mouse astrocytes (funded by a Senior Non clinical Fellowship from the Motor Neurone Disease Association).

  2. Assessing the effect of nutritional supplementation on cortical mouse astrocytes and induced neural progenitor cell derived human astrocytes.

  3. Evaluating the effect of motor neurone disease on the natural metabolic aging process in patient derived cells.

 

Research Funding Awards

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.

Publications

Selected Publications

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.

Biography

2016-Present
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.

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 I 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, I discovered 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. I discovered that these SOD1 and sporadic cases also have higher oxidative stress levels compared to controls. However, incubation with the NRF-2 activator S-apomorphine significantly reduces oxidative stress in a dose dependent manner, providing evidence that S-apomorphine may be an affective therapeutic for MND patients.

Contact Details

Academic Neurology Unit
Department of Neuroscience
SITraN
University of Sheffield
Room B35
385a Glossop Road
Sheffield
S10 2HQ

T: 0114 2222273
E: s.p.allen@sheffield.ac.uk