Degenerative motor neuron diseases are progressive disorders with complex molecular origins that still elude scientists. However, researchers at the University of Toronto believe they may have solved a critical part of the intricate puzzle that leads to Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal dementia (FTD).
ALS is a neuromuscular disease that begins as a mild muscle weakness and progresses to complete paralysis. FTD is closely linked to ALS and leads to memory loss, behavior changes and difficulties with movement and speech. Genetic mutations are known to be an underlying cause of these two disorders, but until now scientists weren't sure how a specific gene caused these devastating diseases.
“Researchers knew that mutations in a specific gene caused 40% of inherited cases of ALS, but there are few studies of the normal function of this gene,” explained senior author Janice Robertson, Ph.D., professor in the department of laboratory medicine and pathobiology at the University of Toronto. “Other scientists have focused on how the gene's mutation causes disease. We've developed the first antibodies to track what this gene does in both a normal and diseased cell.”
Using these newly developed antibodies, Dr. Robertson’s team was able to track proteins from a gene thought to be essential to ALS progression—C9orf72. The investigators discovered that a specific protein from this gene might help transport other essential proteins in and out of a motor neuron cell's nucleus.
The findings from this study were published recently in the Annuals of Neurology through an article entitled “Isoform-specific antibodies reveal distinct subcellular localizations of C9orf72 in amyotrophic lateral sclerosis.”
“We saw that a protein from C9orf72 normally surrounds the nucleus of a motor neuron cell,” said Dr. Robertson. “But in ALS or FTD, this protein moves to the outer membrane of the cell. When this protein is misplaced, it can't help other proteins move in and out of the cell's nucleus, and the cell dies.”
The University of Toronto’s discovery of the mistargeting for the C9orf72 protein in ALS, led them to hypothesize that this gene must be important for nucleocytoplasmic shuttling, which could have a tremendous impact on the pathophysiology of ALD and FTD. Now, the researcher team is looking to understand exactly how C9orf72 is involved in transporting these proteins—with the hope of finding a druggable target in the process.
“This pathway is easily targeted with drugs that already exist,” noted lead author Shangxi Xiao, M.D., Ph.D., research fellow at the University of Toronto. “If we can restore function to this pathway and make proteins go back to the nucleus, we could develop treatment options.”
This study is important as it provides confirmatory evidence nucleocytoplasmic transport may be disrupted in ALS cases, a pathway that has been previously implicated in ALS progression, but also offers novel evidence that protein products of C9orf72 play an important part in this disease pathway.
“Recently, there have been four important publications, all honing in on this specific pathway. We're getting closer to finding treatment options,” Dr. Robertson stated. “Ultimately, our goal is to find a treatment for patients who desperately need more options.”