Peptide helps prevent nerve cell death in MND and dementia

UK scientists have found a way to block the transportation of mutant RNA and subsequent production of toxic repeat proteins that lead to the death of nerve cells in the most common genetic subtypes of motor neurone disease (MND) and frontotemporal dementia (FTD).

The study, led by the Sheffield Institute of Translational Neuroscience (SITraN), also showed that using a peptide to stop the transport of mutant repeated RNA molecules and production of toxic repeat proteins actually increases the survival of C9ORF72 nerve cells — protecting them against neurodegeneration. The findings have been published in the journal Science Translational Medicine.

The Sheffield team previously discovered the abnormal transportation of the rogue RNAs copied from the C9ORF72 gene — known to be the most frequent cause of MND and FTD — is caused by excessive stickiness of a cell transporter named SRSF1. Instead of using conventional drugs which are inefficient in disrupting the stickiness of the SRSF1 protein, or invasive therapies to edit or modulate the activity of defective genes, the new study found that a small peptide incorporating a cell-penetrating module can stick to SRSF1 and effectively block the transportation of the rogue repeat RNA. The peptide is composed of a short chain of amino acids or bricks found within our cells and tissues in the body.

The findings also suggest the peptide could be given to MND and FTD patients orally or in another non-invasive manner; for example, through a nasal spray which could be developed to enter the brain. This concept of using peptides to block the effects of the damaging repeat expanded RNA and toxic repeat proteins could transform how some neurodegenerative conditions which currently have no cure are treated.

“When we tested our innovative approach by adding the peptide to the food eaten by fruit flies not only did the peptides block the damaging mutations which cause MND and FTD from being transported to the cell’s nucleus, we actually saw an improvement in their neurofunction,” said Professor Guillaume Hautbergue, who led the study.

“This means the peptide is effectively blocking the progression of the neurodegenerative condition and also helping to restore the function to the affected nerve cells.

“This concept of using peptides to block destructive mutations unlocks such an exciting and innovative treatment pathway which until now has not been explored by scientists … [and] is a promising alternative to conventional small molecule drugs which are often limited by poor penetration of the blood–brain barrier.”

It is hoped the research, conducted by SITraN in collaboration with the University of Cambridge, the University of Leicester and ETH Zurich, will transform the future of clinical trials for the most common genetic forms of MND and FTD within the next few years.

“This work has provided important evidence in support of a completely new strategy to treat the most common inherited cause of both MND and FTD, with the ultimate goal of developing effective therapies for these devastating diseases,” said Dr Brian Dickie, Director of Research at the MND Association, which co-funded the research.

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