Monday, 9 January 2017

SITraN 2016 review

Happy New Year! A lot happened in 2016, the staff and students here at SITraN have been working to develop disease-modifying therapies for neurodegenerative diseases. There were numerous papers published by SITraN researchers last year (too many to name them all), so this is our yearly recap and summary of a select few…

Deficiency in the mRNA export mediator Gle1 impairs Schwann cell development in the zebrafish embryo
A. Seytanoglu, N. I. Alsomali, C. F. Valori, A. McGown, H. R. Kim, K. Ning, T. Ramesh, B. Sharrack, J. D. Wood, M. Azzouz.
Neuroscience 322 (2016) 287–297

Schwann cells are involved in protecting neuronal axons which are responsible for carrying electrical impulses and information between the body and the brain. They do this by wrapping themselves around axons to produce what is called the myelin sheath; think of the plastic jacket on a cable insulating the wires inside. Using a zebrafish model, the authors found that these Schwann cells were not developing correctly in a nerve when they knocked out a gene called GLE1, which is affected in lethal congenital contracture syndrome 1 (LCCS1). Zebrafish that had no Gle1 had less Schwann cells and therefore less insulation around their nerves and this may be contributing to disease pathology and could be an area of interest to focus research.

The C9orf72 protein interacts with Rab1a and the ULK1 complex to regulate initiation of autophagy

C. P. Webster, E. F. Smith, C. S. Bauer, A. Moller, G. M. Hautbergue, L. Ferraiuolo, M. A. Myszczynska, A. Higginbottom, M. J. Walsh, A. J. Whitworth, B. K. Kaspar, K. Meyer, P. J. Shaw, A. J. Grierson, K. J. De Vos

The EMBO Journal 35 (2016) 1597-1719

A mutation in the C9ORF72 gene is the leading cause of Amyotrophic Lateral Sclerosis and Frontotemporal Dementia (C9ALS/FTD). The function of the C9orf72 protein was, until recently, unknown. One of the proposed theories for how the disease is caused is through reduced levels of the C9orf72 protein. This paper from the De Vos group finds that C9orf72 interacts with another two proteins called Rab1a and ULK1. Both these proteins are involved in a process called autophagy, which is a mechanism used by cells to remove unwanted or damaged parts. Further investigation found C9orf72 is specifically involved in inducing autophagy and when C9orf72 was reduced in cells, autophagy decreased. Finally, when they looked in neurons derived from C9ALS/FTD patients, autophagy appears to be reduced in comparison to healthy controls.

Evaluating a novel cervical orthosis, the Sheffield Support Snood, in patients with amyotrophic lateral sclerosis/motor neuron disease with neck weakness

S. Baxter, H. Reed, Z. Clarke, S. Judge, N. Heron, A. McCarthy, J. Langley, A. Stanton, O. Wells, G. Squire, A. Quinn, M. Strong, P. J. Shaw, C. J. McDermott.

Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration 17 (2016) 436-442

To counter the neck weakness suffered by ALS patients, it is currently advised to wear a neck brace. Feedback from patients however highlighted several issues they faced in doing so, such as their restrictiveness. A project at SITraN was therefore set up to design a neck brace (pictured) that allowed patients more flexibility whilst maintaining its ability to support the neck. This paper from Dr Christopher McDermott’s team describes the response from 26 ALS patients who evaluated the new neck brace. The neck brace was received positively, with key beneficial features described as: increased support while providing a greater range of movement, flexibility of use, and improved appearance and comfort.


Oligodendrocytes contribute to motor neuron death in ALS via SOD1-dependent mechanism
L. Ferraiuolo, K. Meyer, T.W. Sherwood, J. Vick, S. Likhite, A. Frakes, C.J. Miranda, L. Braun, P.R. Heath, R. Pineda, C.E. Beattie, P.J. Shaw, C.C. Askwith, D. McTigue, B.K. Kaspar.
PNAS 113 (2016) E6496-E6505
Oligodendrocytes are cells that help to maintain the health of neurons in the brain and spinal cord. Recent research suggests that oligodendrocytes play a role in ALS. To discover how this happens, the authors of this paper turned cells from ALS patients and healthy individuals into motor neurons and oligodendrocytes, and grew them together in a dish. When ALS oligodendrocytes were grown with healthy motor neurons, the neurons died.  The authors found that SOD1 (a protein known to behave abnormally in many ALS patients) is likely to impair the ability of oligodendrocytes to properly support motor neurons, causing the neurons to die. This research has provided important insights into the toxic role of oligodendrocytes in ALS, which will enable researchers to try and develop therapies to counteract these effects.

Gene expression profiling of the astrocyte transcriptome in multiple sclerosis normal appearing white matter reveals a neuroprotective role

R. Waller, M.N. Woodroof, S.B. Wharton, P.G. Ince, S. Francese, P.R. Heath, A. Cudzich-Madry, R.H. Thomas, N. Rounding, B. Sharrack, J.E. Simpson.
Journal of Neuroimmunology 299 (2016) 139–146

In multiple sclerosis (MS), myelin (an important insulating substance wrapped around axons) in the brain and spinal cord becomes damaged.  Areas of the brain containing myelinated axons are known as “white matter”.  In MS, white matter contains areas that are demyelinated (lesions) and some normal-appearing white matter (NAWM), which is not demyelinated.  This paper aimed to explore the role of astrocytes (supporting cells in the brain) in NAWM.  Some evidence suggests that astrocytes are protective in MS, but other research suggests that astrocytes might contribute to lesion formation.  To better understand the role that astrocytes play in MS, the authors investigated which genes are switched on or off in the NAWM astrocytes of MS patients.   Genes that were upregulated (more switched on) in MS patients compared to controls were associated with supporting neuronal health and controlling responses to oxidative and immune stresses, as well as regulating iron levels, suggesting that NAWM astrocytes are protective in MS.

This blog was written by PhD students Katie Adamson and Yolanda Gibson.
Twitter: @katie_adamson_ @YolandaGibson_

Monday, 19 December 2016

Picturing Parkinson’s Disease. What lies beneath.

My name is Karla and I am a 4th year PhD student in SITraN. I come from Mexico and I work in Professor Oliver Bandmanns group, which focuses on researching Parkinson’s disease.
I recently I won the “Picturing Parkinson´s research” image competition at the Parkinson’s Research UK conference. This competition gave Parkinson´s researchers the opportunity to share insight into their research by using a representative image, accompanied by an engaging description.
My PhD focusses on a protein called TIGAR and understanding its role in Parkinson’s disease. Previous results from our group suggest it is related to the development of the disease. However, this work was done in zebrafish, therefore we wanted to look in the brains of people who had Parkinson’s disease to examine it further and provide a full clinical picture of the disease.
It has been a long journey investigating the mysterious ways that TIGAR might be triggering loss of neurons, which contribute to the problems related to Parkinson’s. We initially looked in a region called the substantia nigra in the human brain, which is the main area that neurons are lost in patients with Parkinson´s disease. From studying this, I decided to enter the competition by sharing this image of the substantia nigra from a Parkinson’s patient. I wanted to represent the tissue as a “desertic field” due to the loss of neurons. However, I also wanted to show the abundance of the protein TIGAR that we see in the remaining cells and in Lewy Bodies, which are abnormal aggregates of protein characteristically seen inside nerve cells of Parkinson’s disease patients.
It is clear from this that there is a relationship between TIGAR and Parkinson’s, however the mechanisms behind this relationship are still unknown.  For me, studying TIGAR in the brains of patients is a way of getting to know each of them personally and enhances my willingness to continue on this journey. In the future I hope to discover the role of TIGAR in Parkinson’s and offer a better therapy for all the people suffering from this relentless illness.   

Monday, 7 November 2016

Year one of my PhD

My name is Becky and I am about to complete the first year of my PhD here at Sheffield Institute for Translational Neuroscience. When I first started I was unsure of what to expect from the next few years and it has definitely been a learning curve! Hopefully by writing these blog posts as I progress through my PhD, I can give you a better idea of what being a PhD student is really like.   

I started learning about neuroscience during my undergraduate degree at the University of Leeds and as a subject it immediately captured my interest. Keen to expand my knowledge in the area, I completed an MRes project at University College London focusing on neurodegeneration. I found this to be such an important area of research that I was eager to continue working within the field for my PhD.

I was lucky to be offered a PhD here at SITraN and I was also incredibly fortunate to secure a University Prize Scholarship. To be chosen to receive this scholarship out of so many outstanding applicants was a huge confidence boost. It reassured me that doing a PhD was the right thing and that I was well suited to the project I chose.

My project is based on the gene C9ORF72, which has been found to be the most common genetic cause of motor neuron disease (MND). MND is a progressive movement disorder that damages motor neurons, which are the nerves which control muscles. This damage prevents important signals between your brain and muscles, causing them to weaken and eventually stop working altogether. Usually this disease is fatal only 2-5 years after diagnosis and there is currently no cure, highlighting the importance of scientific research to better understand MND.

The normal workings of C9ORF72 in the brain are only recently coming to light and my PhD will continue to investigate this. By finding out more about its normal function, we may be able to help unravel the ways in which faults in C9ORF72 can lead to disease. The ultimate goal is that this knowledge could contribute towards finding new life-changing treatments for patients and eventually, a cure.

It has been an intense and challenging experience so far, but I feel like I've learned a lot in the past year. My MRes was a useful introduction to working in a lab, but doing a PhD is such an enormous step up. Throughout a PhD you really have to take ownership of your project and be responsible for the direction it takes – an exciting but slightly daunting prospect! I still have a lot more to learn but I'm really looking forward to seeing where my project takes me.

Friday, 30 September 2016

SITraN goes to a festival!

SITraN goes to a festival!

This September, the University of Sheffield successfully hosted its unique ‘Festival of the Mind’ for the third time since 2012.  Forged in collaboration with Sheffield’s creative and cultural communities, the festival comprises a whole host of events that serve to showcase and celebrate the inspiring research taking place within our University.  Over 11 days, visitors came to venues across the city centre to witness a huge range of research topics being brought to life in the form of art installations, captivating lectures, interactive exhibitions, and much more!

Never being ones to pass up an opportunity to engage the public with the exciting research that we do here at SITraN, a group of staff and students from the department decided to get involved!  Armed with our (very fashionable!) brain T-shirts, we headed down to the Moor Market in Sheffield city centre on Saturday 24th September to deliver lots of fun, neuroscience-themed activities to members of the public.

Over the course of the day, people of all ages visited our stall, where they were able to chat to researchers and discover fascinating facts about the ‘Amazing Brain’.  There were opportunities to look at real-life brains from different animals and learn what makes us as humans more intelligent than mice or birds; people were able to examine slices of brains under the microscope and find out about the important roles of the neurons and other cells that make up our brains; and we got busy with scissors and sellotape, building paper “brain hats” to illustrate the different parts of the brain and the processes that they control in our bodies.

Visitors also had the chance to put their neurons to the test, assessing their reactions and reflexes by trying to catch a falling ruler as quickly as possible, and by trying not to blink whilst wearing lab goggles and having cotton wool balls thrown at their faces (a lot trickier than it sounds!).  Our “mitochondria station” was also a hit: we used electronic circuits to demonstrate how the complex processes that take place in our mitochondria (the tiny, energy-producing powerhouses inside our cells) can become faulty in neurodegenerative diseases like Parkinsons’s disease, and explained how scientists are researching potential treatments for these illnesses by trying to identify and fix these faults.

A fun day was had by all, and it was extremely rewarding and encouraging to see lots of people in Sheffield being inspired by the world of neuroscience research!

Friday, 23 September 2016

Importance of Collaborations

The Importance of Collaborations – A Personal View

This month has seen the publication of two important papers on the genetics of ALS. The first paper describes how variants within three genes (C21orf2, MOBP and SCFD1) which have not previously been linked to ALS have been identified as risk factors for the disease, including in sporadic ALS where there is no family history of disease. The second paper describes how risk variants in NEK1 have been identified in 3% of European and European-American ALS cases. One of the important features of both of these papers is that the results have come about through collaborations, not only nationally, but internationally. Research groups from across the UK, Europe, Turkey, United States and Australia all contributed patient samples to provide the largest cohorts to date for these types of analyses (and these cohorts also included samples collected in Sheffield). This international collaboration is part of an ongoing project “Project MinE” (, which aims to sequence the entire genome of 15,000 ALS patients and 7500 controls. The work is being funded by organisations in each of the contributing countries. In the UK, it is the Motor Neurone Disease Association (MNDA) who is raising the funds to sequence patients DNA and this is where some of the Ice Bucket Challenge money raised in 2014 has been spent.

Many other successful collaborations have also involved the researchers in Sheffield, including European collaborations to understand mitochondrial dysfunction in neurodegeneration (MITOTARGET) and to identify novel therapies through a systems biology approach integrating genetic, environmental, and other –omics data (transcriptomics/proteomics/metabolomics) from patients as well as cellular and animal models (EuroMOTOR). These projects were both funded by the EU and one of the unseen benefits was that this brought together a network of researchers with a range of expertise from across Europe. Subsequently, when the EU Joint Programme for Neurodegenerative Research (JPND) called for projects, the network applied successfully for funding to optimise and harmonise of sampling across the consortia partners (SOPHIA) as well as to discover factors that are associated with risk of ALS and specifically those associated with the rate of progression (STRENGTH).

By understanding the disease better, we are in a stronger position to identify therapeutic targets which could improve quality of life, reduce or stop disease progression, and one day perhaps cure ALS. By working together, joining forces, expertise and resources, it is hoped that these results will come sooner.

 Dr Janine Kirby

Friday, 2 September 2016

ZNstress: A new high-throughput drug screening assay for identifying novel motor neuron disease drugs

I work at the University of Sheffield in Dr Tennore Ramesh’s group based at SITraN. We focus on using zebrafish to model motor neuron disease (MND) and have generated models for many different mutations including SOD1, C9orf72 and TDP-43. My particular focus has been on developing drug screening techniques that use these fish to identify new drugs that treat MND.

Zebrafish are a great tool for investigating neurodegenerative diseases and performing drug screening due to their small size, large numbers, transparency, rapid development and their genetic makeup, which is remarkably close to humans. All these pros allow large drugs screens with 1000’s of drugs to be screened rapidly, something not possible before in animal models of MND.

In our most recent paper we report that we have used the sod1 zebrafish model to screen over 2000 drugs, with the ability to screen 100’s each week. Within this 2000 drugs we tested many drugs from past clinical trials in MND and show that like in the human trials they fail to show efficacy in the zebrafish model. The only drug that showed efficacy was Riluzole, the current MND treatment. We believe that this highlights the true power of using the zebrafish as a drug screening model for MND and we are now working hard to analyse the other 2000 drugs, as well as screening further libraries. We are hoping in the very near future we will have some exciting new potential therapies to talk about that may help towards a cure for MND.

Dr Alex McGown

 To read more about my work :full article

Tuesday, 23 August 2016

Soak a Scientist 2016
It is August 2016, and the researchers in SITraN and members of the South Yorkshire branch of the Motor Neurone Disease Association (MNDA) managed to organise the Soak a Scientist event for yet another year! Running under the hashtag #EveryAugustUntilACure, the event attracted plenty of people who didn’t hesitate to donate to support MND research… And to drench some of our finest scientists!

Monika and I before getting drenched

The seat of destiny, ready for the soaking of scientists.

 shouting and ringing the bell of destiny to attract some audience and donors

The core of the event, like last year, consisted of scientists getting soaked by members of the public for £1 in Endcliffe Park (but only after the scientist rang the bell of destiny, which I had in my custody). Below are some pictures showing how drenched we got that day, and how much my throat got sore after shouting “soak a scientist for a pound!” all day.

There was also a bake sale which became very popular very fast! All our cakes had been baked by SITraN staff, and ranged from yummy chocolate cookies, to delicious Ferrero Rocher-stuffed cake.

Selection of scientists getting soaked, this includes a child how actually paid to get soaked!!

This year, the event also included a tombola and a treasure hunt for children for the first time. A few children got lots of candy after bringing all the very well hidden answers to questions about SITraN, MND and neuroscience, and adults got lots of nice prizes after getting some tickets for the tombola. We were lucky that a lot of businesses around the park donated plenty of prizes which have now found a new home. We also had two visits from journalists who wanted to document the event! One of them published in The Star, and we were interviewed by Sheffield Live!

Jodie and I, explaining some facts about MND and the event.

We raised a fantastic total of £650. This money will be used to buy new equipment for the lab and material for outreach activities. A great outcome after a day packed with water splashes, cake and a lot of really generous people who wanted to help find a cure for MND.

Alejandro Lorente Pons