Researchers at Case Western Reserve University School of Medicine have discovered why one gene, when mutated, is a common cause of two debilitating brain diseases: amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). The study found that the protein generated by this mutant gene, C9ORF72, influences the immune system by regulating the production of interleukin 17A (IL-17A), a potent inflammatory molecule.
The results of research were published in Science Translational Medicine.
New mutant gene related to ALS and dementia
The study found that the protein generated by this mutant gene, C9ORF72, influences the immune system by regulating the production of interleukin 17A (IL-17A), a potent inflammatory molecule.
ALS is a neurodegenerative disease that causes progressive paralysis due to the loss of neurons in the central nervous system. ALS patients often have a pre-existing autoimmune disease and inflammation of the brain that worsens as muscle function declines.
Aaron Burberry, assistant professor of pathology at the School of Medicine and principal investigator of the study, found in mouse models with the C9ORF72 mutation, which affects about 10% of ALS patients, that brain inflammation decreased and mobility improved when the IL-17A gene was blocked.
Burberry and his research team also found that another molecule found in the gut (CD80) contributes to inflammation in response to increased IL-17A in the brain.
“Our research indicates that blocking IL-17A can be rapidly repurposed to treat ALS patients to slow the progression of their disease or possibly prevent ALS from occurring,” Burberry said.
Treatments that block IL-17A have already been approved by the U.S. Food and Drug Administration for the treatment of autoimmune diseases, such as psoriasis and rheumatoid arthritis. These comparable therapies could help ALS patients stop or perhaps reverse the progression of the disease.
“For people living with a neurodegenerative disease,” Burberry said, “our work offers hope for a future in which quality of life and cognitive abilities can be maintained long after diagnosis.”
Burberry will then study the mechanisms by which C9ORF72 inhibits IL-17A in lymphoid cells and identify elements of the gut microbiome that cause inflammation in the brain.
Some people develop amyotrophic lateral sclerosis (ALS), a deadly neurological disorder also known as Lou Gehrig's disease, are prone to autoimmune diseases.
ALS, for which there is no known cure, causes the progressive degeneration of nerve cells in the spinal cord and brain. Approximately 5,000 people are diagnosed with the disease each year.
The new research, conducted by Cedars-Sinai researchers, focuses on a mutation that decreases the expression of a gene called C9orf72, the most common known cause of hereditary ALS.
The researchers found that this mutation, found in about 10% of ALS patients, causes the protein stimulator of interferon genes (STING), a critical sensor of viral infections in the immune system, to become overactive. This hyperactivity led to an increase in interferon production. Interferons are essential for fighting viral infections, but constant and uncontrolled production of interferons can lead to systemic inflammation and the development of autoimmune diseases.
“These findings support that patients with C9orf72 mutations have a fundamentally different set point of their immune system, with an increased propensity for autoimmune diseases and possibly altered responses to viruses and other pathogens in the environment,” said Robert Baloh , M.D., Ph.D. ., professor of Neurology and director of the Cedars-Sinai Center for Neural Sciences and Medicine.
The C9orf72 mutation, which is believed to have originated in Northern Europe about 1,500 years ago and then spread following Viking voyages and wars, is also associated with frontotemporal lobar degeneration, a type of dementia that can accompany ALS.
For the study, the researchers examined brain tissue from laboratory mice with the C9orf72 mutation as well as blood and brain tissue from ALS patients who carry the gene. Results included:
Immune cells isolated from laboratory mice showed early spontaneous activation. Furthermore, a certain type of immune cells, called myeloid cells, had increased production of interferons in response to the activation of the STING protein. Tissues from ALS patients with genetic mutation and frontotemporal lobar degeneration showed an elevated immune response compared to samples from patients with a different type.
Taken together, these findings suggest that patients with the genetic mutation and frontotemporal lobar degeneration have impaired immune systems because their reduced levels of C9orf72 cannot suppress inflammation caused by the hyperactive protein STING, the researchers said.
“These findings provide us with fundamental information about the interaction between the immune system and neurodegenerative diseases,” said Nancy Sicotte, MD, chair of the Department of Neurology at Cedars-Sinai and the Women's Guild Distinguished Chair in Neurology. “They have implications not only for ALS and frontotemporal lobar degeneration, but for other autoimmune and degenerative disorders that affect the nervous system.”
Interestingly, the researchers also found that mice with the C9orf72 mutation were more resistant to certain tumors, likely as a byproduct of an overactive immune system. A similar decrease in tumor incidence has also been reported in ALS patients, but the reason remains a mystery.
“This study combines research on a really important immune pathway and the genetics of ALS, which links neurodegeneration, autoimmune diseases and cancer,” Baloh said.
Baloh's Neurodegenerative Diseases Laboratory is now studying how this genetic mutation and heightened autoimmune response are linked to neurodegeneration. He said understanding these connections can help researchers lay the foundation for developing therapies for ALS.
Harvard University scientists have identified a new gut-brain connection in the neurodegenerative disease amyotrophic lateral sclerosis. The researchers found that in mice with a common genetic mutation, modifying the gut microbiome using antibiotics or fecal transplants could prevent or improve disease symptoms.
The findings provide a potential explanation for why only some individuals carrying the mutation develop ALS. They also point to a possible microbiome-based therapeutic approach.
“Our study focused on the gene most commonly mutated in ALS patients. We made the extraordinary discovery that the same mouse model, with identical genetics, had substantially different health outcomes in our different laboratories,” said Kevin Eggan, professor of stem cell science at Harvard. cellular and regenerative biology.
“We traced the different findings to distinct gut microbial communities in these mice, and now have an intriguing hypothesis as to why some individuals carrying this mutation develop ALS while others do not.”
The researchers initially studied the genetic mutation of ALS by developing a mouse model in their Harvard laboratory. The mice had an overactive immune response, including inflammation in the nervous system and the rest of the body, which led to a shortened lifespan.
To perform more detailed experiments, the researchers also developed the mouse model in their laboratory at the Broad Institute, where Eggan is the director of stem cell biology at the Stanley Center for Psychiatric Research. Unexpectedly, although the mice had the same genetic mutation, their health outcomes were radically different.
“Many of the inflammatory characteristics that we consistently and repeatedly observed in mice at the Harvard facility were not present in mice at the Broad facility. Even more surprising, mice from the Broad facility survived into old age,” said Aaron Burberry, a postdoctoral researcher at Eggan. laboratory and lead author of the study. “These observations spurred our attempt to understand what about the two different environments might contribute to these different outcomes.”
Looking for environmental differences between mice, the researchers delved into the gut microbiome. Using DNA sequencing to identify gut bacteria, the researchers found specific microbes that were present in mice at the Harvard facility but absent in mice at the Broad facility, even though laboratory conditions were standardized across facilities.
“At this point, we reached out to the broader scientific community, because many different groups have studied the same ge
netic mouse model and observed different results,” Burberry said. “We collected microbiome samples from different laboratories and sequenced them. At institutions hundreds of kilometers apart, very similar gut microbes correlated with the extent of disease in these mice.”
The researchers then tested ways to modify the microbiome and improve outcomes for mice at the Harvard facility. By treating mice at the Harvard facility with antibiotics or fecal transplants from mice at the Broad facility, the researchers were able to reduce inflammation.
By investigating the connection between genetic and environmental factors in ALS, researchers have identified an important gut-brain connection. The gut microbiome could influence disease severity – whether individuals with the genetic mutation develop ALS, the frontotemporal dementia-related condition, or no symptoms – and could be a potential target for therapy.
“Our study provides new insights into the mechanisms underlying ALS, including how the most common genetic mutation contributes to neural inflammation,” Eggan said. “The gut-brain axis has been implicated in a number of neurological conditions, including Parkinson's disease and Alzheimer's disease. Our findings add weight to the importance of this connection.”
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