A group of researchers led by J. Paul Taylor, M.D., Ph.D. at St. Jude Children’s Research Hospital and Rosa Rademakers, Ph.D., of the Mayo Clinic in Jacksonville, Florida have discovered fundamental pathology behind ALS popularly known as Lou Gehrig’s disease. They have identified biological process that kills neurons in amyotrophic lateral sclerosis (ALS) and in frontotemporal dementia (FTD), a related genetic disorder. The findings of the research has been published in the journal “Neuron”.
Unlike in other genetic diseases, the disease causing mutation does not cripple an enzyme in a biological regulatory pathway but produces protein involved in phase separation in cells. Phase separation refers to a mechanism through which proteins assemble into membrane-less organelles necessary for orderly functioning of cells. Scientists found that ALS or FTD mutation produces a protein called TIA1 that makes up the organelles. Consequently, in ALS, proteins accumulate and kill neurons that control muscles and in FTD, such accumulation kills neurons in the brain.
Although there is presently no treatment available for ALS or FTD which can be called effective, researchers believe that their discovery can assist in developing treatments to restore neuron’s ability to disassemble the organelles. Analysing the genes of family affected with ALS or FTD helped in discovery of TIA1 mutation which alters the properties of highly mobile “tail” of the protein. The region under tail is governed by the ability of the protein to assemble with other TIA1 proteins. In the past, Taylor and his team identified such unstructured protein regions (also known as prion-like domains) as the hotspot for disease causing mutations and building blocks of cellular assemblies.
Scientists revealed that TIA1 mutations occurred frequently in ALS patients and people carrying the mutation had the disease. On investigating the brain tissue of deceased ALS patient with mutations, scientists found TIA1 containing organelles called stress granules in the neurons formed when the cell experienced stresses such as heat, chemical exposure and aging. In order to survive, the cell isolates or hides away in the granules’ genetic material which is responsible for coding for cell proteins not necessarily for survival-critical processes. Granules contain a protein called TDP-43 whose abnormality has implications in causing ALS. Studies found that TIA1 mutation causes the protein to become more “sticky,” delaying disassembly of stress granules, trapping TDP-43.
Taylor mentions that these findings offer highly promising ways for developing effective treatments for ALS or FTD that would prevent neuronal damage in the cells of people with ALS or FTD mutations. In further studies, Taylor and his team seek to understand the process of phase transition and map the regulatory machinery for stress granules to seek therapeutic targets since similar pathology of phase transition may underlie other neurodegenerative diseases.
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H/T: Medical Xpress