Remarkably, they also uncovered TAF15 and EWSR1 mutations in ALS patients that were not found in healthy individuals. Based on these findings, they proposed that RNA-binding proteins with prion-like segments might contribute very broadly to the pathology of ALS and related brain disorders.
Characterizing the Top-Ten
Taylor, Gitler, Shorter, and others continued to characterize the top-ten human RNA-binding proteins with prion-like segments. The Nature study describes that two more of the top-ten candidates, called hnRNPA1 and hnRNPA2B1, are mutated and cause familial cases of brain disease. The mutations in hnRNPA1 and hnRNPA2B1 were present in two families with an extremely rare inherited degeneration affecting muscle, brain, motor neuron, and bone and another from a person with familial ALS.
Mutations in these two proteins fell in the prion-like segments and coincided with "sticky" regions in the proteins, making these regions more prone to assemble into self-organizing fibrils. The normal form of the proteins shows a natural tendency to assemble into fibrils, which is exacerbated by the disease mutations.
"The mutations accelerate the formation of the fibrils that recruit normal protein to form more fibrils," noted co-first author Emily Scarborough, from Penn. This dysregulated assembly likely contributes to disease. Indeed, the disease mutations also promote excess incorporation of the proteins into stress granules within a cell and the formation of clumps in the cells of animal models of human neurodegenerative disease.
|Contact: Karen Kreeger|
University of Pennsylvania School of Medicine