Neuroscientists on Mayo Clinic’s campus in Florida have found an aberrant protein is a key toxic culprit in the most prevalent form of familial amyotrophic lateral sclerosis (ALS). Publishing in Nature Medicine, the research team found the protein, known as poly(GR), accumulates in neurons and interferes with the creation of normal cellular proteins, causing the neurons to die. “Poly(GR) is produced from a mutation in c9orf72, which occurs in nearly half of patients with familial ALS,” says the study’s principal investigator, Leonard Petrucelli, Ph.D., chair of the Department of Neurosciences in Florida. “In this study we identified how poly(GR) causes toxicity to cells.”

Leonard Petrucelli, Ph.D.

The c9orf72 mutation, which was discovered by a team at Mayo Clinic in 2011, is the most common known cause of familial ALS, and even crops up in 10 percent of sporadic cases of the disease. ALS is a motor neuron disease that affects nearly 20,000 people nationwide. The same mutation also occurs in nearly one third of patients with frontotemporal dementia (FTD), an early-onset behavioral disorder that affects nearly 250,000 Americans. Even though ALS and FTD do not always overlap in patients, the genetic overlap suggests similar mechanisms might be at play in both diseases.

Using a novel mouse model that they developed, Dr. Petrucelli’s team found that poly(GR) binds to components of ribosomes, molecular machines that produce proteins necessary for the proper function and survival of cells. Poly(GR) was also found to impair the ability of neurons to mount a proper response to cellular stressors, ultimately causing a state of chronic cellular stress and the death of neurons. “When we looked at poly(GR) in human brain cells, we observed the same phenomenon,” says first author Yong-Jie Zhang, Ph.D.

Understanding the effect of poly(GR) will direct future studies, particularly in developing treatments for patients with ALS and FTD who have the c9orf72 mutation. Strategies may focus on reducing poly(GR) or preventing it from interfering with normal protein production. “Our next steps will be to try to find ways to alleviate the stress poly(GR) causes in cells,” says Dr. Petrucelli.

The Mayo Clinic research team includes: Yong-Jie Zhang, Ph.D., Tania F. Gendron, Ph.D., Mark T. W. Ebbert, Ph.D., Aliesha D. O’Raw, Mei Yue, Karen Jansen-West, Xu Zhang, Ph.D., Mercedes Prudencio, Ph.D., Jeannie Chew, Ph.D., Casey N. Cook, Ph.D., Lillian M. Daughrity, Jimei Tong, Yuping Song, Sarah R. Pickles, Ph.D., Monica Castanedes-Casey, Aishe Kurti, Rosa Rademakers, Ph.D., Bjorn Oskarsson, M.D., Dennis W. Dickson, M.D., Wenqian Hu, Ph.D., Aaron D. Gitler, Ph.D. (Stanford University School of Medicine), John D. Fryer, Ph.D.

The study was funded by the National Institutes of Health, the Mayo Clinic Foundation, the Robert Packard Center for ALS Research at Johns Hopkins, the Amyotrophic Lateral Sclerosis Association, and the Target ALS Foundation.