Researchers discover fundamental pathology behind ALS

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A team led by scientists at St. Jude Children's Research Hospital and Mayo Clinic has identified a basic biological mechanism that kills neurons in amyotrophic lateral sclerosis (ALS) and in a related genetic disorder, frontotemporal dementia (FTD), found in some ALS patients. ALS is popularly known as Lou Gehrig's disease.

In further studies, the researchers found that TIA1 mutations occurred frequently in ALS patients. The scientists also found that people carrying the mutation had the disease. When the investigators analyzed brain tissue from deceased ALS patients with the mutations, the scientists detected a buildup of TIA1-containing organelles called stress granules in the neurons. Such granules form when the cell experiences such stresses as heat, chemical exposure and aging. To survive, the cell sequesters in the granules' genetic material that codes for cell proteins not necessary for survival-critical processes.

The granules also contained a protein called TDP-43, another building block of stress granules, whose abnormality has been implicated in causing ALS. In test tube studies and experiments with cells, the researchers found that the TIA1 mutation causes the protein to become more "sticky," delaying the normal disassembly of stress granules, trapping TDP-43.

"This paper provides the first 'smoking gun,' showing that the disease-causing mutation changes the phase transition behavior of proteins," Taylor said. "And the change in the phase transition behavior changes the biology of the cell."

"We know that these material properties are under tight regulation, so perhaps we don't have to target the disease-causing mutation itself," Taylor said. "Perhaps we can restore balance by targeting any of a large number of regulatory molecules in the cell. There are already therapeutic approaches in laboratory testing that seek to do just that."