Stress Granules May Be Key to ALS and Related Diseases

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Scientists at St. Jude Children’s Research Hospital may have unlocked the key to understanding amyotrophic lateral sclerosis (ALS) and other similar diseases of the nervous system. The study, titled Phase Separation by Low Complexity Domains Promotes Stress Granule Assembly and Drives Pathological Fibrillization,” appeared in the September 24th issue of the journal Cell. The research may ultimately provide new methods for treating ALS.

In ALS (also known as Lou Gehrig’s Disease), nerve cells that control movement progressively die in the brain and spinal cord. This causes muscle weakness, paralysis, and eventually loss of breathing and death. Unfortunately, there is no current cure for the disorder, and very limited treatment options. Research into new possible treatments for the disease is greatly needed.

A region of a specific protein known as hnRNPA1 can become mutated in ALS and other nervous system diseases. hnRNPA1 binds to RNA and can cause the formation of stress granules, which are created when cells are under strain from various factors, potentially having detrimental effects (a stress granule occurs due to a failed attempt of the cell to create a protein from an mRNA).

Led by Amandine Molliex, a graduate student, researchers demonstrated that under specific temperatures as well as salt and protein concentrations, hnRNPA1 can create droplets that resemble stress granules. The protein-rich droplets form through a process known as “liquid phase separation.”

“This study provides the mechanism that links stress granules, toxic fibrils and disease,” remarked principal author, J. Paul Taylor, M.D., Ph.D., a Howard Hughes Medical Institute (HHMI) investigator and chair of the St. Jude Department of Cell and Molecular Biology. “In addition to advancing our understanding of fundamental cell biology, the results have spurred interest in developing drugs that target the stress granule assembly process.”

The investigators further demonstrated how hnRNPA1 mutations are related to stress granule-like protein droplets, promoting the formation of toxic fibrils which are similar to the toxic amyloid protein fibrils observed in Alzheimer’s disease as well as in other neurological conditions.

The group suggests that stress granules can be reversed at some point, but if they persist it can result in disease and protein fibrilization. The work could lead to some general principals that help guide the development of novel treatments for several different diseases. “Rather than attempting to target each disease-causing mutation, these findings have generated interest in developing drugs that target the stress granule assembly process,” Taylor noted.