Dr. Scott Allen describes his work on identifying the role of dysfunctional energy generation in neurodegenerative conditions like Motor Neuron Disease
Seeking Metabolic Therapies for an Incurable Neurodegenerative Disease
Dr. Scott Allen is a Senior Non-Clinical Fellow at the Sheffield Institute for Translational Neuroscience. In 2018, he shared with us a discovery that inspired his own scientific research, and he received a travel award from STEMCELL Technologies to attend a conference of his choice. He chose to attend the European Network to Cure ALS (ENCALS) meeting 2018 with his student Mr. Ryan Woof.
I think that scientific discoveries go hand in hand with technological developments. Without these radical advancements in technological and engineering capabilities, many of the recent discoveries would not have been achievable. From a neuroscience perspective, the ability to study human central nervous system cells in the laboratory has revolutionized how we study diseases such as motor neuron disease, Parkinson's disease, and Alzheimer's disease. This has only come about as a result of the fantastic work by Shinya Yamanaka who was able to revert a differentiated cell to a pluripotent state using transcription factors. This gives researchers the ability to take patient skin cells and reprogram them into CNS cells such as neurons. We can now study human neurological diseases in primary human-derived cells that we would not have had access to, and decrease the reliance on the use of animal models.
Dr. Scott Allen, University of Sheffield, United Kingdom
Science moves forward when you share it with the world. So we asked Dr. Allen and Mr. Woof to share their research, and their experience at the ENCALS conference.
The Research: Dysfunctional Energy Generation in Neurodegenerative Conditions
Can you tell us about your research?
The main research focus of my group is identifying the role of dysfunctional energy generation in neurodegenerative conditions, with a particular interest in Motor Neuron Disease (MND). MND is an adult onset, incurable neurodegenerative disorder, involving death of motor neurons in the brain and spinal cord, that leads to muscle dystonia (a disorder characterized by uncontrollable muscle contractions), paralysis, and death. Many patients suffer from disrupted energy generation in the central nervous system contributing to the disease pathogenesis.
Our primary aim is to develop metabolic therapeutic strategies by:
- Using phenotypic metabolic screening with an OmniLog™ metabolic profiling system (Biolog Inc.) to identify novel metabolic targets for therapeutic intervention.
- Develop nutritional supplementation regimes for people with MND to support motor neuron health, and slow down the disease progression.
We use various in vitro cell models, including primary patient cells, genetically reprogrammed human progenitor cells and stem cells expressing green fluorescent protein, to identify and functionally analyse metabolic targets of interest. We then test these targets in vivo by nutritionally supplementing zebrafish models of MND and measuring neuronal stress. We use this approach to assess how MND affects metabolic pathway regulation and interaction, how metabolism responds to disease specific cellular stress such as oxidative stress and hypoxia, and how the disease affects the metabolic response to aging in patients.
In your research, to which lineage do you differentiate cells?
We generate induced neuronal progenitor cells (iNPCs) from skin cells using direct conversion methods, so it’s a lineage switch, which retains the aging phenotype as it does not reset the epigenetic state of the cell. iNPC-differentiated astrocyte lines have been compared with laser captured astrocytes from the post mortem spinal cord of patients and fibroblast lines through gene array analysis. The results show that iAstrocytes from iNPCs share over 80% of transcripts in common with human laser captured astrocytes. iAstrocytes not only share more similarities with post mortem astrocytes than fibroblasts, but they also show very similar expression patterns. The iAstrocytes also express high levels of GFAP, various glutamate transporters (EAAT1 and 2) and several other glial markers, including Aldh1l1, CD44, and S100b.
Which genes or pathways are affected in MND?
The body's natural energy balance of intake and expenditure is disrupted in MND patients. This occurs in both sporadic and familial cases with mutations in SOD1, TDP43, FUS, or intronic expansions in C9orf72. The normal balance between energy intake and expenditure is tipped towards expenditure in MND patients. This hypermetabolism coupled with defective energy-generating pathways in cells, including mitochondrial dysfunction, glycolytic dysfunction, fatty acid metabolism dysregulation, nucleoside dysfunction, and oxidative stress, leads to a bioenergetic deficit that contributes to disease pathogenesis. Patients are typically slim, have a low body mass index, and they lose both weight and body fat as the disease progresses, due to higher energy expenditure than expected. Alterations in energy metabolism, including insulin resistance, altered levels of free fatty acids, and perturbations in lipid homeostasis, have been reported both in patients and transgenic animal models of MND. Moreover, patients with type 2 diabetes appear to have delayed MND onset suggesting that an altered metabolism can have a beneficial effect in patients.
The Conference: ENCALS 2018, Oxford, England
Why did you choose to attend the ENCALS conference?
ENCALS is one of the major global ALS/MND conferences held annually. Many of the top academic scientists attend. It is a good conference for early career scientists to attend as it is quite relaxed and the principal investigators are very approachable.
As it was my first conference and I was presenting a poster, I was quite nervous going into it. However, after sitting through a few talks and attending the poster session on the first evening, it settled my nerves seeing how relaxed and friendly the environment was.
Mr. Ryan Woof, University of Sheffield
Can you tell us about your favorite presentations at the conference?
One of my favorite talks of the weekend was titled 'Using patient-derived astrocytes to unravel the role of misfolded SOD1 in sALS cases' [presented by Noemi Gatto, The University of Sheffield]. The talk was about methods of obtaining astrocytes by reprogramming fibroblast skin cells into induced neuronal progenitor cells, and then ultimately into astrocytes. After allowing time for the iNPCs to differentiate into astrocytes in 5 - 7 days, they can then be used for testing in the laboratory. It is interesting to see the scientific steps of how these astrocytes are obtained from fibroblasts, because this topic is directly related to my project on SOD1.
Another of my favorite presentations was 'The ENCALS debate'. This was a nice way to finish off the second day of talks. It was an interactive debate about whether ALS is a prion-like disease. Two 15-minute talks were presented from both sides of the argument with the aim to win the support of the audience. At the end, everybody voted through an app. It was a good and uplifting way to finish the day, and it kept me and others entertained throughout as the speakers kept the audience involved.
This conference allowed me to experience first-hand what goes on within the scientific community around the world outside of our laboratory. It was eye opening to see how much work goes on across different aspects of the disease, and how ultimately everyone is doing their own part, working together to cure ALS. It allowed me to speak to other more experienced researchers, and share the findings from my current project with them whilst listening to their research and their feedback.
Mr. Ryan Woof, University of Sheffield
Dr. Allen’s work is funded by:
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Scott Allen, PhD