Mutations in the C9orf72 gene is the most common known cause of frontotemporal dementia (FTD) and hereditary amyotrophic lateral sclerosis (ALS), a progressive neurodegenerative disease that rapidly affects motor neurons in the brain and spinal cord, which stop sending messages to muscles, causing muscle weakening and inability to move. Mutations of this gene in patients cause both the production of toxic proteins and the decrease in the expression of the C9orf72 gene.

The researcher of the University of Valencia Alberto Yáñez collaborates in this study that the journal Nature has just published and is led by the laboratory of researcher Robert Baloh of the Institute of Regenerative Medicine, the Department of Neurology and the Center for Neural Sciences and Medicine of Cedars-Sinai Medical Center Hospital, in Los Angeles (USA).

“In previous research, published in the journal Science, we demonstrated an unexpected role for C9orf72 in the regulation of the immune system. This was interesting, as patients with FTD/ALS tend to develop autoimmune diseases, but the reason for this increased risk in these patients was still unclear”, says Alberto Yáñez.

In the study now published by Nature, they show that C9orf72 regulates the function of STING, a critical sensor of viral infections within the innate immune system. Yáñez Boyer explains that what they observed in a mouse model “is that the loss of C9orf72 causes STING to become hyperactive inducing a large systemic inflammation. In addition, we found a similar overactive inflammatory signal in the blood and tissues of ALS patients carrying the C9orf72 mutation. We finally found that we could suppress this overactive inflammation using a STING inhibitor”, explains the UV researcher.

The co-author of the paper published in Nature concludes that “these findings reveal that patients with C9orf72 mutations have a fundamentally altered immune system, with a tendency to autoimmunity and an altered response to viruses and other environmental pathogens. This study suggests that inhibiting STING activation could be a new therapeutic strategy for treating patients with FTD/ELA carrying C9orf72 mutations”.

Article: McCauley, M.E., O’Rourke, J.G., Yáñez, A. et al. C9orf72 in myeloid cells suppresses STING-induced inflammation. Nature (2020). 

https://doi.org/10.1038/s41586-020-2625-x