New Research Suggests Autoimmune Diseases in FTD/ALS Linked to C9orf72 Mutation

Robert Baloh, MD, PhD, at work in his laboratory. Photo by Cedars-Sinai.

The findings of a new study focused on the C9orf72 mutation could help to explain why some people who develop FTD and/or ALS are seemingly more susceptible to autoimmune disorders.

Recognized as the most common genetic cause of both hereditary FTD and ALS, the C9orf72 mutation may cause either or both conditions in carriers, but it is still unclear as to what determines that development. Disease-causing mutations in the gene usually result in a lack of functional C9orf72 protein, which is thought to influence the production of RNA within cells.

The study, led by a team of Cedars-Sinai investigators, found that a certain type of immune cell, called myeloid cells, showed signs of increased inflammatory activity in mice lacking a functional C9orf72 gene. More specifically, the myeloid cells had increased production of interferons, which are key for fighting viral infections. While integral to the body’s immune defense system, constant, uncontrolled production of interferons can lead to systemic inflammation and development of autoimmune diseases.

Further analysis revealed that the increased interferon production was the result of abnormal activity of the STING (Stimulator of Interferon Genes) protein, one of many proteins that immune cells use to detect possible threats, such as viruses and cancer cells. Taken together, the findings suggest that people with FTD and/or ALS who harbor the mutation have an altered immune system because their reduced levels of the C9orf72 cannot suppress inflation caused by the hyperactive STING protein, according to investigators.

“These findings support that patients with C9orf72 mutations have a fundamentally different set point of their immune system, with increased propensity to autoimmune diseases, and probably altered responses to viruses and other pathogens in the environment,” study co-author Robert Baloh, MD, PhD, director of the Cedars-Sinai Center for Neural Science and Medicine, said in a press release.

Baloh is now studying how this gene mutation and heightened autoimmune response is linked to neurodegeneration. Understanding these connections may help investigators lay the groundwork for developing therapies for ALS, he said in the release.

To read more about the study, click here.

Photo by Cedars-Sinai: Robert Baloh, MD, PhD, at work in his laboratory.

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