It is known that Amyotrophic Lateral Sclerosis (ALS) gradually kills nerve cells in the brain and spinal cord. It is one of the most prevalent neuromuscular diseases, resulting in more than 5,600 new diagnoses in the U.S. each year. Around 10% of those diagnoses are caused by the mutation of the C9orf72 gene with studies suggesting that about 500,000 people in the U.S. are carriers of the mutation.
Recent studies show that the mutation interferes with normal expression of the protein made by C9orf72, however the function of that protein is unknown, and as with every mutation that has been associated with ALS, it remains unclear how the C9orf72 mutation causes ALS. Now, a study from researchers at Cedars-Sinai shows that immune cells in the brain play a direct role in the development of or ALS, offering hope for new therapies to target the neurodegenerative disease that gradually leads to paralysis and death. The team state that their findings represent an important step toward understanding the role of this particular genetic mutation and enables new understanding about the causes of ALS. The study is published in the journal Science.
Previous studies show that mutations in the C9orf72 gene cause ALS, a condition characterized by progressive muscle weakness, a loss of muscle mass, and an inability to control movement. These mutations affect the GGGGCC segment of the gene and when this series of nucleotides is repeated too many times, it can cause ALS. This type of mutation is called a hexanucleotide repeat expansion. Although it is not clear exactly how many hexanucleotide repeats are needed to cause disease, researchers believe that having more than about 30 repeats can lead to ALS. It is also unclear whether the hexanucleotide repeat expansion reduces C9orf72 protein function or leads to the production of a protein with abnormal function that disrupts RNA and protein production in the cell, resulting in the formation of protein clumps. The current study shows that C9orf72 is required for the normal function of myeloid cells, and altered microglial function may contribute to neurodegeneration in C9orf72 expansion carriers.
The current study utilised two genetic strains in mice lacking the C9orf72 gene. Results show that instead of developing ALS, mice without the gene unexpectedly suffered immune system abnormalities. Data findings show that structures within immune cells, known as lysosomes, that normally dispose of unwanted cellular material stopped functioning properly without the C9orf72 gene.
Results show that the C9orf72 gene is critical for the function of immune cells in the brain, adding to growing evidence that the brain’s immune system actively contributes to disease rather than simply responding to injury. The lab state that their data continues a paradigm shift in the way the global medical community think of how brain cells are lost in conditions like ALS and Alzheimer’s disease.
The team surmise that their findings may point the way to new therapies to target immune cell dysfunction, particularly in patients carrying the C9orf72 gene mutation. They go on to add that drugs aimed at decreasing levels of the gene should also be approached with caution because they could further disrupt the immune system. For the future, the researchers state that their work opens the possibility that C9orf72 gene carriers may even respond differently to immune-modulating drugs, as opposed to ALS patients lacking this gene.