Bengaluru: A study by IISc scientists has uncovered how mutations in “DDX3X”, a gene linked to one of the most common genetic causes of intellectual disability in women, can damage brain cells. The findings also point to a cellular process that may be involved in diseases such as Alzheimer’s.DDX3X is a protein that helps cells process RNA and respond to stress. Normally, when a cell is under stress, DDX3X and other proteins gather with RNA into temporary structures called stress granules. These act as holding areas while the cell deals with the problem. Once the stress passes, they dissolve.Researchers found that disease-causing mutations in DDX3X disrupt this process. Instead of forming temporary structures that disappear, the altered protein can become trapped in persistent, solid-like stress granules.This means that a system designed to help the cell cope with stress ends up disrupting the cell itself. The abnormal structures interfere with normal neuronal function and eventually trigger the death of brain cells.The study, led by Kesavardana Sannula of the Department of Biochemistry, combined computer modelling with lab experiments to understand how the mutations produce this effect. The researchers found that the mutations change how DDX3X interacts with RNA, altering the protein’s behaviour inside cells.The findings provide the first molecular explanation of how different mutations associated with DDX3X syndrome can converge on a common pathway of neuronal damage. The researchers also found that some disease-associated mutations promote the aggregation of beta-amyloid, a protein whose accumulation is a hallmark of Alzheimer’s disease.The finding does not mean that DDX3X mutations cause Alzheimer’s. Instead, it adds to growing evidence that abnormal protein-RNA structures inside cells may play a role in several neurological disorders. When these normally temporary structures stop being dynamic and persist, they can interfere with the functioning and survival of neurons.The discovery could also influence how DDX3X syndrome is treated. Rather than focusing only on restoring the normal activity of the DDX3X protein, future therapies could try to prevent the abnormal stress granules from forming or help them dissolve normally.DDX3X sits on the X chromosome; since females have two X copies, they often survive these mutations, whereas the effect in males is frequently more severe or lethal. DDX3X syndrome can cause intellectual disability and a range of developmental and neurological problems, and researchers have identified many mutations associated with it.The IISc study suggests that these apparently different mutations may ultimately push cells towards the same damaging state. The work, therefore, offers more than an explanation for a rare genetic disorder. It provides a glimpse into how a cellular mechanism meant to protect brain cells during stress can, when disrupted, become a cause of neuronal death.
