Unravelling the mystery of the most common genetic cause of motor neuron disease

Researchers from the Sheffield Institute for Translational Neuroscience (SITraN) have shed light on how mutations in a high risk gene specifically affect motor neurons.

Motor NeuronScientists at the flagship motor neuron disease research centre, based at the University of Sheffield, investigated how specialised nerve cells that control voluntary movements die – something which is key to understanding motor neuron disease (MND).

The study, which is now published in PLOS ONE looked at changes that specifically occur in motor neurons in the most common genetic cause of MND linked to mutations in the C9ORF72 gene.

They have found evidence that repetitive sequences found within this gene in people with MND can be toxic and lead to a widespread malfunction of gene expression.

The ribonucleic acid (RNA) copies produced from the C9ORF72 gene in MND patients are faulty, and instead of being used to produce the C9orf72 protein they cause mayhem in the cell.

They accumulate in speckles termed RNA foci and by binding and hording nuclear processing and export factors, they affect the correct expression of other genes.

The researchers conclude that this may not immediately result in disease; however in time compensatory mechanisms might be overwhelmed in vulnerable cells.

SITraN researcher Dr Johnathan Cooper-Knock, a Lady Edith Wolfson Fellow supported by the MND Association and the Medical Research Council (MRC), said: ..

“We have studied gene expression profiles in isolated motor neurons derived from MND patients and controls, and have identified an up-regulation of genes encoding proteins involved in genetic editing, so-called RNA splicing. Furthermore, despite this up-regulation which may be an attempted compensation, we identified an increased error rate in RNA splicing.”

“Making errors is probably a normal occurrence, but patients with the gene mutation make so many that over time they become toxic. In fact it was shown that patients with the highest error rate had the most severe disease.”

Studying tissue from C9ORF72-MND patients the researchers also found that motor neurons, the prime targets in MND, accumulate a distinct type of RNA produced from the C9ORF72 gene. The faulty gene sequence is copied in both directions, termed ‘sense’ in the direction of the gene and ‘antisense’ referring to the reverse copy.

The study now published in Acta Neuropathologica concludes that antisense foci are present at a significantly higher frequency in motor neurons than in other nerve cells studied. Moreover, the presence of antisense foci, but not sense foci, correlated significantly with nuclear loss of the protein TDP-43 which is the hallmark of MND neurodegeneration.

The scientists also observed antisense foci in the cytoplasm of motor neurons, which is consistent with defective export of the faulty RNA copies from the nucleus, and may be a key step in the production of toxic protein derived from the antisense RNA.

“This intriguing observation suggests that antisense RNA foci may occupy a key position in the cascade of disease pathogenesis in C9ORF72 MND,” added Dr Cooper-Knock.

"We suggest that the key to toxicity might be a propensity to produce antisense foci mediated by cell-specific transcriptional regulation events in motor neurons.”

Professor Dame Pamela Shaw, Director of SITraN and lead of the MND research team, said: “This has implications for translational approaches to C9ORF72 disease and furthermore, interacting RNA-processing factors and transcriptional activators responsible for antisense versus sense transcription might represent novel therapeutic targets.”

Additional information

Cooper-Knock J, Higginbottom A, Stopford MJ, Highley JR, Ince PG, Wharton SB, Pickering-Brown S, Kirby J, Hautbergue GM, Shaw PJ. Antisense RNA foci in the motor neurons of C9ORF72-ALS patients are associated with TDP-43 proteinopathy. Acta Neuropathol. 2015 May 6; http://link.springer.com/article/10.1007%2Fs00401-015-1429-9

Cooper-Knock J, Bury JJ, Heath PR, Wyles M, Higginbottom A, Gelsthorpe C, Highley JR, Hautbergue G, Rattray M, Kirby J, Shaw PJ. C9ORF72 GGGGCC expanded repeats produce splicing dysregulation which correlates with disease severity in amyotrophic lateral sclerosis. PLOS ONE, 27 May 2015, http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0127376

The Sheffield Institute for Translational Neuroscience (SITraN)
SITraN is a world-leading research centre purpose-built and dedicated to research into motor neuron disease (MND/ALS) and related neurodegenerative diseases including Parkinson’s disease, Alzheimer’s disease, and stroke. The state-of-the art research facility was opened in 2010 by HM The Queen and uniquely allows the multidisciplinary collaboration of clinicians, scientists and health professionals to develop new treatments for the benefit of patients.
To find out more visit www.sheffield.ac.uk/sitran/

The University of Sheffield
With almost 26,000 of the brightest students from around 120 countries, learning alongside over 1,200 of the best academics from across the globe, the University of Sheffield is one of the world’s leading universities. A member of the UK’s prestigious Russell Group of leading research-led institutions, Sheffield offers world-class teaching and research excellence across a wide range of disciplines. Unified by the power of discovery and understanding, staff and students at the university are committed to finding new ways to transform the world we live in. In 2014 it was voted number one university in the UK for Student Satisfaction by Times Higher Education and in the last decade has won four Queen’s Anniversary Prizes in recognition of the outstanding contribution to the United Kingdom’s intellectual, economic, cultural and social life. Sheffield has five Nobel Prize winners among former staff and students and its alumni go on to hold positions of great responsibility and influence all over the world, making significant contributions in their chosen fields. Global research partners and clients include Boeing, Rolls-Royce, Unilever, AstraZeneca, Glaxo SmithKline, Siemens and Airbus, as well as many UK and overseas government agencies and charitable foundations.

The Motor Neurone Disease Association
The MND Association was founded in 1979 by a group of volunteers with experience of living with or caring for someone with MND.
It is the only national charity in England, Wales and Northern Ireland focused on MND care, research and campaigning. Motor Neurone Disease (MND), also known as Amyotrophic Lateral Sclerosis (ALS)

  • MND is a fatal, rapidly progressive disease that affects the brain and spinal cord.
  • It attacks the nerves that control movement so muscles refuse to work. Sensory nerves are not usually affected.
  • It can leave people locked in a failing body, unable to move, talk and eventually breathe.
  • It affects people from all communities.
  • It kills around 30% of people within a year of diagnosis, and more than 50% within two years.
  • It has no cure.

For more information visit: www.mndassociation.org


For further information, or to speak with Dr Cooper-Knock, please contact:

Dr Monika Feigenbutz
SITraN Communications Officer
University of Sheffield
0114 222 2250

Amy Pullan
Media Relations Officer
University of Sheffield
0114 222 9859