Researchers link mechanism with two diseases

USC researchers recently discovered a cellular mechanism that accounts for at least 10 percent of each amyotrophic lateral sclerosis (ALS) and frontotemporal dementia cases.

The gene mutation in the C9 gene increases the risk of ALS and frontotemporal dementia cases. Photo from USC Keck School of Medicine News Release.

The mechanism limits the number of “cellular janitors,” like lysosomes, in the nervous system leading to increased risk for the two neurodegenerative diseases.

Yingxiao Shi and Shaoyu Sebastian of the Justin Ichida Laboratory at USC said that a mutation in a gene labeled “C9ORF72” leads to toxicity in nerve cells, which is a factor in at least 10 percent of both ALS and frontotemporal diseases.

The C9ORF72, or C9 gene, produces a protein required to make lysosomes that grab and remove toxic proteins and garbage, according to Ichida, an assistant professor of stem cell and regenerative medicine at the Keck School of Medicine. It acts as a cellular chain reaction. Without a normal number of lysosomes, the motor nerve cells collect toxic garbage, which includes a large toxic protein produced by the C9 mutation and molecules that receive signals from the glutamate and die.

“We figured out how the most common form of ALS causes nerve cell death, and nerve cell death is what causes patients to become paralyzed or lose control of neuromuscular functions,” Ichida said in a news release from Keck.

To understand the process, the researchers removed blood from ALS patients carrying the C9 mutation and reprogrammed these blood cells into motor nerve cells that degenerate and die in the disease, according to the news release. In addition, they extracted blood from healthy patients, reprogrammed these blood cells into motor nerve cells and used gene editing to delete the C9 gene, according to the news release.

Both groups with the mutated motor nerve cells had a reduced number of proteins normally made by the C9 gene. By adding the supplemental C9 protein, the researchers were able to stop the motor nerve cells from degenerating.

The Ichida Lab is now using the patient-derived motor nerve cells to test potential drugs, focusing on those that affect lysosomes. They are looking to find potential drugs that slow or stop degeneration of these motor nerve cells, and hope to eventually use these drugs on patients, according to the news release.