Identification of drugs that limit the toxicity of arginine-rich peptides might provide new clues to potential therapies for ALS

In a recent study published in Cell Chemical Biology, researchers from the Oscar Fernandez-Capetillo group at Karolinska Institutet have identified drugs that limit the toxicity of peptides causing the neurodegenerative illness ALS. This might provide new clues to potential therapies.

Oscar Fernandez-Capetillo, who has led the study at the Department of Medical Biochemistry and Biophysics answers some questions about their new findings.

What are the most important results from your study?

Recent work identified that mutations linked to amyotrophic lateral sclerosis (ALS), a terrible neurodegenerative disease that currently lacks a cure, lead to the production of some repeated proteins which accumulate at nucleoli and kill mammalian cells.

This seminal work has triggered significant enthusiasm in the biomedical research community since, in principle, if we learn how to limit the toxicity of these peptides we might have a new treatment for ALS. In our study we have searched for chemical compounds capable of reducing the toxicity of ALS-associated peptides, and identified some drugs capable of doing so.

While at this point we do not have a full understanding of how these chemicals mitigate the toxicity of ALS-peptides, we have seen that they rescue the nucleolar alterations induced by the peptides. Hence, I would say that the two most important results from our study are:

• the identification of drugs that limit the toxicity of ALS-related peptides, and
• suggesting that strategies oriented to limit nucleolar stress might be of interest in the context of neurodegenerative diseases.

How can this new knowledge contribute to improving human health?

As there is no cure to ALS today, patients only receive treatments that have no significant impact on survival rates. Recent works have identified mutations in C9ORF72 as the most frequent genetic cause of ALS and frontotemporal dementia (FTD), and these mutations were shown to lead to the production of toxic dipeptide repeats which kill cells.

In our work we provide a panoramic view of how most medically approved compounds or drugs at an advanced stage of development affect the toxicity of ALS-related peptides. Importantly, we report that some of these compounds can rescue the toxicity of ALS-related peptides both in cells in culture and also in fish.

If this toxicity plays an important role on ALS pathogenesis, our work might provide new clues to potential therapies for this devastating disease.

How did you perform the study?

To conduct the study, we exploited our expertise in high-throughput microscopy, to perform a chemical screen looking for drugs capable of rescuing the cell death caused by ALS-related peptides. We analyzed the effects of around 4200 compounds and found some capable of reducing the toxicity of these peptides.

We subsequently investigated how these compounds could rescue the toxicity of the peptides, and found that they did so by preventing the nucleolar alterations induced by these toxins.

Finally, we tested if the effects we observed in human cancer cells were also conserved in more disease-relevant systems such as motoneuron-related cell lines or live animals (fish), and found that this was indeed the case.

Altogether, our study involved chemical screens, cell biology and the use of fish as a disease model, which collectively helped us to identify potential new strategies for the treatment of ALS.

Publication

A chemical screen identifies compounds limiting the toxicity of C9ORF72 dipeptide repeats
Alba Corman1,*, Bomi Jung1,*, Maria Häggblad1, Lars Bräutigam2, Vanesa Lafarga3, Louise Lidemalm1, Daniela Hühn1, Jordi Carreras-Puigvert1, Oscar Fernandez-Capetillo1,3,4
Cell Chemical Biology, online 6 december, doi: https://doi.org/10.1016/j.chembiol.2018.10.020