Study Identifies Key Mechanism Connecting Stress Granules, Toxic Fibrils, and Degenerative Diseases Like ALS and FTD; Involvement of hnRNPA1 Protein and Its Long Disordered Tail Is Crucial; Results Suggest Benefit of Targeting Stress Granule Formation

St. Jude Children's Research Hospital scientists have discovered evidence of a mechanism at the heart of amyotrophic lateral sclerosis (ALS) and related degenerative diseases. The research appears in today's September 24, 2015 issue of Cell and highlights a possible new treatment strategy for the devastating disorders. The article is titled “Phase Separation by Low Complexity Domains Promotes Stress Granule Assembly and Drives Pathological Fibrillization.” The St. Jude’s study focused on usually short-lived compartments called stress granules that form in cells under stress. Stress granules are just one type of the membrane-less structures or organelles that assemble as needed to handle various cell functions and then rapidly disperse. Until now, however, the mechanism underlying stress granule formation was poorly understood. Stress granules are also tied to degenerative disorders such as ALS, which is also known as Lou Gehrig's disease. Genes encoding the protein components of stress granules are often mutated in patients with ALS and other diseases. These same proteins accumulate in thread-like deposits called amyloid fibrils in the nerve and muscle cells of patients with ALS, frontotemporal dementia (FTD), and inclusion body myopathy (IBM). But the unifying mechanism was a mystery. "This study provides the mechanism that links stress granules, toxic fibrils, and disease," said co-corresponding 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.
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