A recent study, published in Science Translational Medicine, describes a novel way to prevent the death of nerve cells in patients with motor neurone diseases and frontotemporal dementia. The potential new treatment uses a small peptide molecule to prevent the transport of mutant RNA and the subsequent production of toxic proteins.
A repetitive problem
Amyotrophic lateral sclerosis (ALS), the most common form of motor neurone disease, and frontotemporal dementia (FD) are both caused by the presence of a hexanucleotide repeat in the C9ORF72 gene. The neurodegenerative symptoms associated with these conditions are thought to arise due to the translation of the mutant C9ORF72 RNA into toxic dipeptide repeat (DPR) proteins that contribute to the death of nerve cells. This process occurs following the sequestration of the repeated RNA with the SR-rich splicing factor 1 (SRSF1) protein. SRSF1 subsequently binds with nuclear export factor 1 (NXF1) to transport the mRNA out of the nucleus, ready for translation. Currently, there is no cure for either condition, and effective treatments remain scarce.
Following on from previous research carried out in their lab, Guillaume Hautbergue and his team from the University of Sheffield investigated whether a small peptide molecule could be used to prevent the translation of DPR proteins and rescue the neurodegenerative phenotype both in vivo and in vitro.
Modelling the effects
The small peptide in question was designed as a competitive inhibitor that fits into the SRSF1:NFX1 binding site, in order to prevent the interaction between the two proteins and the subsequent movement of the toxic C9ORF72 RNA. In patient-derived cells, the peptide was successful in performing this function, ultimately decreasing the production of the toxic protein and even increasing the survivability of the cells.
Figure 1: Image of a DAPI stain showing the number of DPR proteins found in untreated cells, and those cultured in different concentrations of the peptide molecule (WT-CPP). The number of DPRs appears to decrease as concentration to the drug is increased. Adapted from Castelli et al., 2023.
To test whether this result translated in vivo, the team chose to orally administer the molecule to the model organism Drosophila melanogaster. The researchers observed a stark decrease in the presence of DPR proteins in C9ORF72 mutant fruit flies, and a decrease in further neurodegeneration. In fact, exposure to the drug improved the insects’ motor function, implying that prevention of DPR protein translation could restore nerve cell functions. The molecule’s effectiveness was further proven in a mammal model, with an injection into the brains of mice leading to a decrease in the number of toxic proteins present. No toxic side effects were observed in any aspect of the study.
Restoring function
Describing the study, Hautbergue stated: “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.” With no cure available for either of these devastating neurological conditions, it is vital to investigate potential treatments. This study shows that there is great potential for the development of a peptide-based drug that could be administered orally, that could not only prevent further disease progression but reverse damage that has already occurred.
