Researchers have zeroed in on a protein that is linked to ALS that could be the answer to finding new drugs to treat the debilitating disease.
A team from Brown University has described for the first time the atom-by-atom changes in a family of proteins linked to ALS, a group of brain disorders known as frontotemporal dementia and degenerative diseases of muscle and bone.
The aim of the research will be to target the cellular pathway with a drug or other therapy to prevent the diseases from occurring.
“There is currently no therapy or cure for ALS and frontotemporal dementia,” Nicolas Fawzi, the study’s senior author from Brown, said in a statement. “We are pursuing new hypotheses and angles to fight these illnesses.”
Several proteins linked to ALS contain low-complexity domains or pieces, which are squirmy and disordered, while the cell’s best understood proteins are ordered and static in structure. The rigid shape of the proteins are flexible and float inside cells until cued into action.
“Because these low-complexity domains are too flexible to be directly targeted by standard drugs, finding out how cells use and tame these domains is a potential route to stopping their unwanted assembly in disease,” Fawzi said.
In non-disease situations, low-complexity domains help proteins perform healthy functions, including assembling into liquid-like droplets, where cellular processes, including RNA processing, take place.
However, when low-complexity domains go awry, as in disease, they transform into inclusions, intractable and accumulating knots or clumps. In various cancers, the low-complexity domains are improperly attached to other proteins that may then incorrectly form droplets in cellular locations, leading to mis-regulated expression of genes.
“We’re trying to understand why they change behavior and aggregate, and how we can disrupt those processes,” Fawzi said. “We show how small chemical changes–involving only a few atoms—lead to big changes in assembly and disease-associated aggregation.
“These interactions are more dynamic and less specific than previously thought,” he added. “A molecule does not take just one shape and bind to one shape but a molecule is flexible and interacts in flexible ways.”
Cells divide their function within organelles—distinct cellular structures. The researchers examined hnRNPA2, a protein that is mutated in disease and collects in membrane-less organelles, where they may use their low-complexity domain to stick together.
The researchers used nuclear magnetic resonance spectroscopy, computer simulations and microscopy to show how disease mutations and arginine methylation—a functional modification common to al arge family of proteins with low-complexity domains—altered the formation of the liquid droplets and their conversion to solid-like states in disease.
The study was published in Molecular Cell.
Filed Under: Drug Discovery
