C9ORF72 gene mutations drive inflammatory molecule’s production
Repurposing protein's inhibitors eyed as possible therapeutic approach
Mutations in the C9ORF72 gene may lead to amyotrophic lateral sclerosis (ALS) and the related disorder frontotemporal dementia (FTD) in part by boosting the production of a powerful inflammatory protein called interleukin 17A (IL-17A), recent preclinical research suggests.
Inhibiting IL-17A via genetic manipulations or medications was associated with lowered inflammation and motor performance gains in mice who lacked C9orf72, offering a possible therapeutic approach for both conditions that could be achieved by repurposing IL-17A inhibitors already approved for certain inflammatory conditions.
“Our research indicates that IL-17A blockade may be quickly repurposed to treat ALS patients to slow down the progression of their disease or possibly stop ALS from ever occurring,” Aaron Burberry, PhD, assistant professor at Case Western Reserve University in Ohio and the study’s senior author, said in a university press release. “For people living with a neurodegenerative disease … our work offers hope for a future where quality-of-life and cognition can be maintained long after their diagnosis.”
The study, “Myeloid and lymphoid expression of C9orf72 regulates IL-17A signaling in mice,” was published in Science Translational Medicine.
Mutations in C9ORF72 are the most common genetic cause of ALS and FTD, neurodegenerative diseases marked by the progressive loss of key nerve cells in the brain and spinal cord. Such mutations are implicated in up to 50% of familial ALS cases, up to 10% of sporadic ALS cases, and up to around 30% of cases of FTD.
Exploring C9ORF72 gene’s role in ALS, FTD
While the exact role of C9ORF72 in ALS isn’t well established, its protein product, C9ORF72, is prevalent in the brain and is believed to be important for nerve cell function and communication. It’s also found in the immune system.
Brain inflammation and evidence of autoimmunity — where the immune system attacks healthy tissue — is a feature of these neurodegenerative diseases and is often evident even before the onset of neurological symptoms.
Still, the mechanisms by which this autoimmune-like profile arises haven’t been fully established. Previous research has implicated a possible role for C9ORF72 in ALS-associated autoimmunity.
Here, the scientists explored the gene’s possible role in modulating these immune processes by genetically engineering mice to lack C9orf72 in various hematopoietic cell types, which encompasses all the cell types found in the blood, including immune cells.
A loss of the gene in myeloid cells, those from the innate immune system that are produced in the bone marrow, led to signs of severe autoimmunity. In turn, its deficiency in lymphoid cells, immune cells that defend the body from specific threats, led to increased IL-17A production and an excess of immune neutrophil cells.
In mice lacking C9orf72, certain myeloid immune cell subsets, including macrophages and monocytes, which are found in circulation, and in microglia, their brain-resident relatives, had increased levels of the CD80 protein on their surface. CD80 elevations were also observed in microglia from the spinal cord of people with C9ORF72-mediated ALS relative to people without ALS. The protein modulates immune function and has been implicated in some inflammatory diseases of the gastrointestinal system.
The research indicates C9ORF72 normally works to suppress IL-17A production in lymphocyte cells and to prevent CD80 trafficking to the myeloid cell surface in response to the signaling of IL-17A and other inflammatory molecules. When the gene is lacking or dysfunctional, these inflammatory activities may become amplified.
Consistent with these observations, deleting the gene encoding IL-17A in C9orf72-deficient mice prevented CD80 elevations in the spinal cord, reduced neutrophil counts, and lowered the number of a certain type of immune cells in the gut. And treatment with an anti-IL-17A antibody improved motor function and suppressed inflammation in the C9orf72-deficient mice.
The findings “provide support for IL-17A as a therapeutic target for neuroinflammation associated with ALS or FTD,” the researchers wrote.
Medications to block IL-17A, the brand names of which include Cosentyx and Taltz, are already approved in the U.S. for certain autoimmune diseases.
Burberry’s research team plans to examine the mechanisms by which C9ORF72 normally works to inhibit IL-17A in lymphoid cells and to identify the specific microorganisms and molecules in the gut that contribute to inflammation in the brain.
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