Sheffield Institute for
Translational Neuroscience


New Target to fight Motor Neurone Disease using gene therapy uncovered by Neuroscientists at the University of Sheffield

  • New mechanism discovered in the most common genetic cause of MND opens up a novel field for potential therapeutic intervention
  • Alleviating Motor Neurone Disease (MND) is central to the research carried out at the Sheffield Institute for Translational Neuroscience (SITraN)
  • In work funded by the MND Association, a breakthrough has been achieved in collaboration with the MRC Mitochondrial Biology unit of Cambridge the Nationwide Childrens Research Institute in Ohio and the UCL Institute of Neurology in London.

Every day six people in the UK die from Motor Neurone Disease, which causes progressive paralysis as the nerves supplying muscles degenerate for reasons that are incompletely understood. At any one time nearly half a million people worldwide suffer with this devastating condition but in the majority of cases it is not known what causes the nerves supplying muscles (the motor neurons) to die. The commonest known cause is a mutation in a gene called C9ORF72. About 1 in 10 cases of MND is linked to having an expanded repeating region of DNA in a part of the C9ORF72 gene that is not usually made into protein.

Delving into the molecular core of how the products of this gene behave in the cell, in work published today in Nature Communications, scientists at SITraN have discovered a key pathway in C9ORF72-linked MND. Tests in patients’ cells and in fruitfly models of MND indicate that targeting this pathway is a novel angle to tackle the degeneration of nerve cells (neurodegeneration) that occurs in MND.

Lead author Dr Guillaume Hautbergue has studied the molecular biology of RNA for over 25 years and spent 10 years from 2002 – 2012 in the department of Molecular Biology and Biotechnology at the University of Sheffield in Professor Stuart Wilson’s laboratory developing methods to study the mechanisms that export messenger RNA from the nucleus to the cell cytoplasm. There, Dr Hautbergue established the accepted model of how this works in humans before taking up a lectureship in Translational Neuroscience at SITraN. Translating advances in fundamental discovery science into real benefits for patients is the raison d’etre for SITraN so it is very satisfying that harnessing Dr Hautbergue’s developments in the field of RNA biology has now led to the discovery of a new therapeutic strategy of neuroprotection in MND and potentially other neurodegenerative diseases. 

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From left to right: Dr’s Guillaume Hautbergue, Lydia Castelli and Laura Ferraiuolo  contributed equally to this work that was jointly supervised by Dr Guillaume Hautbergue, Dr Alexander Whitworth from the MRC Mitochondrial Biology Unit at the University of Cambridge and Prof Dame Pamela Shaw from the Sheffield Institute for Translational Neuroscience (below). 


The corresponding authors of the study are Dr Guillaume Hautbergue ( and Dr Alex Whitworth ( 

While the main purpose of DNA is to code for proteins to be built in the cell, we know that a lot of DNA doesn’t code for protein after all, such as the repeating region of the C9ORF72 gene. In healthy versions of the gene the repeated region (usually under 30 repeated units) is simply cut out of the RNA copy of the gene before the RNA is exported from the nucleus.

In C9ORF72-MND however, the repeated region is much larger – even up to a thousand repeated units and leads to a build up of the RNA repeats inside the nucleus but also, unexpectedly is made into abnormal toxic constituents in the cell cytoplasm called dipeptide repeat proteins. The discovery of dipeptide repeat proteins was puzzling to scientists as this type of non-protein coding RNA does not normally exit the nucleus to get to where protein can be made.

Dr Hautbergue and colleagues, who have developed expertise in the mechanisms of RNA nuclear export, looked to see how the pathological repeating precursor RNA molecules, that should be confined to the nucleus, might be getting exported to the cell cytoplasm where the toxic protein is made. It turned out that just one component of the nuclear-cytoplasm transport system, a protein called SRSF1, was responsible for shuttling the RNA repeats out the door of the nucleus into the cytoplasm. Crucially, the breakthrough in this discovery is that SRSF1 is only needed to help the pathological C9ORF72 RNA to exit the nucleus. All other, useful protein coding RNAs can get to the cytoplasm without it. Partially removing SRSF1 from the cell in fruitfly models and cultures of cells from MND patients using gene therapy (see the Spotlight on Technology box in yellow for more on the techniques used in this work) had no adverse effects  in the models tested and prevented the toxic dipeptide repeats from being formed. This is the first time that the nuclear export of pathological repeating RNAs has been elucidated in a neurodegenerative disease and the first time that it is shown that targeting this pathway provides a promising therapeutic strategy of neuroprotection.

Interestingly a number of other genes that cause neurodegenerative diseases including Huntington’s disease, Fragile-X associated Tremor/Ataxia Syndrome, Myotonic Dystrophy and other disorders affecting muscle co-ordination contain similar repeat expansions as those found in the C9ORF72-MND gene. So looking at whether those expansions are turned into toxic proteins and whether this can be prevented through turning off a specific nuclear exporter too, might open up a whole new area of research into treating neurodegenerative disorders. A patent application was filed for the use of SRSF1 antagonists in the treatment of neurological disorders. 


RNA Explained


The fundamental pathway in biology is that information flows from the DNA code; a genetic ‘blueprint’ for proteins – the building blocks of life, to microscopic cellular machinery that produce proteins to order from a pool of amino acids in the cytoplasm of the cell. The DNA supplying the recipe of instructions to make a particular protein is too large to get from where it is housed in the nucleus of the cell out to where the protein producing machines are located outside the nucleus, so the message is sent via a messenger molecule called RNA. RNA takes a copy of the blueprint coded instructions from the DNA out of the nucleus to where proteins can be produced in a process called ‘translation’. Regions of DNA that are not translated into protein are still copied into RNA but then usually cut out of the final RNA molecule that is exported out of the nucleus.

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Spotlight on Technology

Two cutting-edge techniques were deployed in the work that led to this breakthrough. First, to look at the disease mechanisms inside individual patient’s neurons (nerve cells) a specially devised method developed in Ohio by Dr Laura Ferraiuolo was used to reprogram skin cells taken from a small skin biopsy into neurons, the specialised cells of the nervous system that cannot be easily accessed to study in life. Animal models of disease are extremely useful to scientists to test new theories and treatments but have the limitation of being simplified versions of disease made from a uniform model whereas a genetic disease like MND can present more variably in humans that are genetically more diverse from one another. This is thought to be one reason why new therapies that give promising results in animal models have failed to perform as well in patients on clinical trials. The fruitflies used in this research all had an identical 36 number of the pathological C9ORF72 repeated units inserted into their DNA. In patients with C9ORF72-MND however, the number of repeats can vary very widely from just over 30 to over 1000 units. It could have been the case that SFSR1 only transported low number repeat expansion pre-RNA out of the nucleus. Testing out the strategy in cells actually derived from patients powerfully indicates that the approach will be relevant in the real disease.

The gene therapy approach used in the research took a therapeutically engineered virus to get an RNA molecule inside the cell that would interfere with RNA for the production of SFSR1. Interfering RNA prevents the targeted protein from being produced. Effectively knocking-down the amount SFSR1 in the cell stopped the toxic C9ORF72 dipeptide repeat protein from being formed and rescued the cell from neurodegeneration. Gene therapy using viruses is extremely effective as the virus can stay inside the cell and continuously produce the therapeutic interfering RNA over a long period of time for the ongoing treatment of a genetic disease. Dr Hautbergue and colleagues Prof Mimoun Azzouz and Prof Pamela Shaw at SITraN are currently in talks with companies such as AveXis Inc. and Pfizer to take forward a translational gene therapy program and a new PhD student starting in September will be trying out the strategy in a mouse model of C9ORF72-linked MND.