Researchers at St. Jude Children's Research Hospital and Mayo Clinic have identified a key mechanism that kills neurons in amyotrophic lateral sclerosis (ALS) and a related disorder, frontotemporal dementia (FTD), found in some ALS patients. These findings may have major implications for one day treating these diseases.
Published yesterday in the journal Neuron, the study reports that a mutation in a protein called TIA1, which is involved in cell phase separation, can lead to the development of ALS/FTD. When TIA1 is mutated, proteins accumulate inside membrane-less organelles, cellular components necessary for orderly cell functions. In ALS, these accumulated proteins cause neurons that control the muscles to be killed whereas in FTD the neurons that control the brain are killed.
After the initial discovery, studies confirmed mutations of TIA1 to be more frequent in patients with ALS/FTD. Furthermore, when brain tissue from deceased ALS patients was analyzed, buildups of TIA1-countaining organelles called stress granules were found in the neurons. These stress granules also contain TDP-43, a protein which previous studies had already linked to ALS/FTD pathology.
According to J. Paul Taylor, M.D., Ph.D., one of the lead authors of the study, "These findings are part of an emerging theme that there is a whole spectrum of diseases that includes ALS, and some forms of dementia and myopathy, that are caused by disturbance in the behavior of these structures that perturbs cellular organization."
The authors hope this research may someday lead to improved treatment for these disorders. While current drugs to treat ALS seek to improve the function of already damaged neurons, these findings may provide a basis for restoring healthy balance of phase separation in those with ALS/FTD mutations. Future research will focus on finding targets for treatment as well as exploring the role of phase transition in other neurodegenerative diseases, such as Alzheimer’s.