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Breakthrough disease mechanism behind Amyotrophic Lateral Sclerosis (ALS) uncovered

Researchers at UK Dementia Research Institute at King’s College London and ETH Zürich found a new role for RNA in the development of a neurodegenerative disease.

Brain jigsaw with a puzzle piece taken out and laid next to it

Frederic Allain from ETH Zürich, reported a discovery providing a new insight into the molecular basis of the neurodegenerative disease Amyotrophic Lateral Sclerosis. The study uncovered a previously unknown mechanism in the gene involved in this devastating disease. This discovery may serve as a basis to develop new therapies.

Amyotrophic Lateral Sclerosis (ALS) is a fatal disease that causes progressive weakness of the muscles due to the degeneration of motor neurones in the brain and spinal cord. The average age at onset is 60 years and death usually occurs three years after the first symptoms appear, due to respiratory failure. Although there are some treatments available that can slow the progression by a few months, those affected are in desperate need of more effective therapeutics that improve symptoms and extend life expectancy.

In 5% of ALS cases, the root cause is genetic, and scientists have identified that mutations in the FUS gene can cause an early-onset form of the disease. The FUS protein plays a crucial role in the normal functioning of our cells, binding RNA molecules to fine-tune the process that manufactures proteins from our DNA. In individuals who have mutations in the FUS gene, proteins are seen to build up in the wrong location, proving toxic to cells such as the motor neurones. However, the specific details of this process have remained elusive and until fully understood, are a barrier to the development of treatments.

Dr Marc-David Ruepp and his team set about investigating the detailed biological steps behind this process in the hope that opportunities to therapeutically intervene and stop the disease may become apparent. Using cutting-edge methods, they looked for differences in how normal and mutant FUS bind to RNA molecules in the cell and discovered an abnormal interaction with a key RNA that causes the latter’s mis-localisation and build up. These findings provide the first mechanistic and atomic resolution insights into how a toxic interaction of FUS with RNA could contribute to motor neurone degeneration, and offers hope for the generation of new treatments for individuals with the mutated form of the protein.

The discovery that mutant FUS undergoes toxic interactions with specific RNAs is exciting, especially because mutations in numerous RNA binding proteins are known to cause ALS. We hope that our insights will pave the way towards a better understanding of the disease and result in novel therapeutic approaches.– Dr Marc-David Ruepp, Group Leader at UK DRI at King’s College London and a senior author of the paper

Study first author Dr Daniel Jutzi added,“In this collaborative work, we established how exactly the FUS protein binds to central RNA molecules in the cell. Besides improving our understanding of the biological function of FUS, this knowledge will allow us to create synthetic RNAs to target FUS for therapeutic intervention.”

Another important finding in this study also revealed a shared mechanism between ALS and another neurodegenerative disease called spinal muscular atrophy (SMA). This indicates the significance of the biological mechanism and how it can be used as therapeutic target.

Aberrant interaction of FUS with the U1 snRNA provides a molecular mechanism of FUS induced Amyotrophic Lateral Sclerosis – Jutzi et al is published today in Nature Communications DOI: 10.1038/s41467-020-20191-3

Contact 

For interviews or any further media information please contact:

Louise Pratt, Head of Communications, IoPPN: louise.a.pratt@kcl.ac.uk / +44 7850 919020

Amy Edmunds, UK DRI Director of Communications and Engagement: amy.edmunds@ukdri.ucl.ac.uk

Adapted from UK DRI News

In this story

Marc-David Ruepp

Marc-David Ruepp

Senior Lecturer in Neuroscience