New insight into the most common genetic cause of amyotrophic lateral sclerosis and frontotemporal dementia

• Novel function uncovered for the C9orf72 protein that is linked to amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD)
• Groundbreaking research could pave the way to for potential future drug development

Scientists from the University of Sheffield have discovered a novel function of the C9orf72 protein which is linked to amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) - giving a new insight into the most common genetic cause of the degenerative diseases.

Autophagosomes in Hela cellsThe pioneering study, conducted by researchers from the world-leading Sheffield Institute of Translational Neuroscience (SITraN), found that the C9orf72 protein, which is encoded by the C9ORF72 gene, functions in the autophagy pathway – something which is defective in patients with the most common inherited form of ALS and FTD.

Mutations in the C9ORF72 gene carry a well-established risk for ALS, also known as motor neurone disease (MND), and FTD which is the second most common cause of dementia in people under 65. However, until now the basis for this link has been unclear.

Scientists believe one of the ways the C9ORF72 mutation may cause ALS and FTD is by reducing the amount of C9orf72 protein present in the cells – something which is very hard to verify without a clear understanding of the function of the C9orf72 protein.

The Sheffield team led by Dr Kurt De Vos and Dr Andy Grierson investigated the role of the C9orf72 protein in nerve cells and found it regulates the initiation of a vital process called ‘autophagy’, which helps the cell to dispose of damaged proteins and cell parts, and recycles cell nutrients.

Dr De Vos said: “Our study provides compelling evidence that the C9orf72 protein is required for the initiation of autophagy, a pathway essential for the survival of nerve cells.

“We could also show that that loss of C9orf72 protein function mimics the specific pathology observed in our ALS and FTD patients.”

Dr Andy Grierson, fellow lead investigator, added: “Diseases such as ALS and FTD are commonly associated with large protein clumps that accumulate in affected nerve cells. Our data now shows that the C9orf72 protein is involved in the cellular pathway that should dispose of these clumps and that the autophagy process is defective in the cells of our ALS and FTD patients.

“Further studies are needed to confirm if defective autophagy contributes to the disease process, but if this bears out then autophagy drugs may be beneficial for patients.”

The pioneering study, published in the EMBO Journal was supported by the Thierry Latran Foundation, Medical Research Council (MRC), MND Association, Alzheimer’s Society, European Union and the University of Sheffield Moody Endowment Fund.

Dr Valerie de Broglie, Director of the Thierry Latran Foundation, said: “We are pleased to see the positive outcome of the research selected by our European Scientific Advisory Board. Better understandings of pathways involved in ALS are of upmost importance to move towards a therapy.”

Dr Doug Brown, Director of Research at Alzheimer’s Society, said: “Frontotemporal dementia is the second most common form of dementia in those under the age of 65, and can include some upsetting symptoms, yet we know relatively little about its underlying causes.

“This study reveals what happens in the brain cells of people with a gene mutation that is known to cause frontotemporal dementia. Identifying the effects of faulty genes is a vital first step to being able to design drugs that could best help people living with the condition. The gene, known as C9ORF72, was only linked to dementia in the last five years so it’s encouraging that advances are being made to piece together the important role it plays in the brain.”

Dr Sadie Vile, Research Grants Manager at the MND Association, added: “Although only about 10 per cent of MND cases are inherited, study of the genetic causes helps to understand the non-inherited or sporadic forms. The C9ORF72 gene was identified in 2011 as the most common cause (about 40 per cent) of all inherited MND.

“The autophagy process has been linked to other MND-causing genes, so it is interesting that evidence is now building up to connect this important cellular process to the C9orf72 protein. We are very proud that Emma Smith, one of our MND Association PhD students, has played a key role in this important piece of research.”

Additional information

Reference: Webster CP, Smith EF et al (2016) ‘The C9orf72 protein interacts with Rab1a and the ULK1 complex to regulate initiation of autophagy’. EMBO Journal. DOI: 10.15252/embj.201694401

The Thierry Latran Foundation
The Thierry Latran Foundation is a non-profit organization set up under the aegis of Foundation de France. It is the first and sole pan European research foundation dedicated to ALS research with the aim to contribute to the development of a therapy for ALS. To this end, the Foundation has two goals: to establish a European ALS research community and to fund excellent research projects. Since its inception in 2009, the Foundation has funded 46 projects to a total of 6.2 million Euros, and has organized seven annual meetings to monitor on-going projects and promote collaborations. To find out more please visit:

Alzheimer’s Society
Alzheimer’s Society is the UK’s leading dementia support and research charity. 850,000 people in the UK have a form of dementia. In less than ten years a million people will be living with dementia. This will soar to two million people by 2051.
Alzheimer’s Society funds research into the cause, care, cure and prevention of all types of dementia and has committed to spend at least £150 million on research over the next decade.
For more information please visit:

The Motor Neurone Disease (MND) Association
The Motor Neurone Disease (MND) Association is the only national charity in England, Wales and Northern Ireland focused on MND care, research and campaigning. Motor neuron disease (MND) is a fatal, rapidly progressing disease that affects the brain and spinal cord. It attacks the nerves that control movement so muscles no longer work. MND does not usually affect the senses (sight, sound and feeling). It can leave people locked in a failing body, unable to move, talk and eventually breathe. Some people may experience changes in thinking and behaviour, with a proportion experiencing a rare form of dementia (FTD). It kills a third of people within a year and more than half within two years of diagnosis. Six people per day are diagnosed with MND in the UK. There is no cure. Amyotrophic lateral sclerosis (ALS) is the most common form of MND, with both upper and lower motor neuron involvement. For more information see

The Sheffield Institute for Translational Neuroscience (SITraN)
SITraN is a world-leading centre for research into neurodegenerative diseases including motor neurone disease (MND/ALS), Parkinson’s disease and Alzheimer’s disease. The purpose-built facility 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

The University of Sheffield
With almost 27,000 of the brightest students from over 140 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. Sheffield is the only university to feature in The Sunday Times 100 Best Not-For-Profit Organisations to Work For 2016 and was voted number one university in the UK for Student Satisfaction by Times Higher Education in 2014. In the last decade it 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.


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Amy Pullan
Media Relations Officer
University of Sheffield
0114 222 9859