Scientists Identify Disease-Causing Mutation of ALS, Frontotemporal Dementia

The findings offer a new pathway for developing treatments for diseases such as amyotrophic lateral sclerosis.

Scientists have identified a basic biological mechanism behind motor neuron death in patients with amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD).

The first-of-its-kind identification of this mutation showed it produces an abnormal version of a protein involved in the cell process phase separation, a mechanism by which proteins assemble into organized membrane-less organelles that are necessary for cell function.

In a study published in Neuron, investigators found the ALS/FTD mutation produces an abnormal version of TIA1, a protein that is a building block of these organelles. As a result, the proteins in the organelles accumulate, killing off the motor neurons in ALS patients. In FTD, the accumulation kills neurons in the brain.

The investigators discovered the TIA1 mutation while analyzing the genomes of a family affected with ALS/FTD. After tracing the mutation’s effect on TIA1’s structure, they found that it altered the properties of a highly mobile “tail” of the protein.

These regions are prion-like domains that govern the protein’s ability to assemble with other TIA1 proteins. In prior studies the investigators identified these regions as the building blocks of cellular assemblies and hotspots for disease-causing mutations.

Upon further research, the investigators found that TIA1 mutations frequently occurred in patients with ALS, and that individuals carrying the mutation had the disease.

After analyzing the brain tissue of deceased ALS patients with the mutations, they detected a buildup of stress granules in the neurons. Stress granules form when cells are exposed to heat, chemicals, and aging. The cell then sequesters genetic material in the granules that codes for cell proteins not needed for survival.

Furthermore, they investigators found the granules contained another building block: the TDP-43 protein. Abnormalities in TDP-43 has been implicated in the cause of ALS.

The investigators conducted test tube studies and experiments with cells and found the TIA1 mutation causes the protein to become sticky, delaying the normal disassembly of stress granules that results in the trapping of TDP-43.

“This paper provides the first ‘smoking gun,’ showing that the disease-causing mutation changes the phase transition behavior of proteins,” said lead investigator Paul J. Taylor, MD, PhD. “And the change in the phase transition behavior changes the biology of the cell.

“These findings are part of an emerging theme that there is a whole spectrum of diseases that include ALS, and some forms of dementia and myopathy, that are caused by disturbance in the behavior of these structures that perturbs cellular organization.”

ALS is a neurodegenerative disease that affects the nerve cells in the brain and spinal cord. As the neurons die off, the muscles begin to atrophy. Patients will eventually lose their ability to walk, speak, swallow, and breathe. Currently, there is no known cure and the average life expectancy from diagnosis is 2 to 5 years.

These findings offer a promising step to an effective treatment for ALS/FTD, according to the authors. Current treatments seek to improve the function of already damaged neurons; however, the new findings suggest the potential for treatments that prevent neuronal damage by restoring the healthy balance of phase separation in cells of patients with ALS/FTD mutations.

“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 the large number of regulatory molecules in the cell. There are already therapeutic approaches in laboratory testing that seek to do just that.”

For future studies, the investigators plan to gain a better understanding of the basic process of phase transition, and map the regulatory machinery of stress granules for potential therapeutic targets.