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In a study published in “Cell” on Aug.13, Yale researchers identified a defect in a cell structure called the mitochondria to be a cause of a rare genetic disorder called “fragile X syndrome.” 

Led by Associate Research Scientist in Medicine Pawel Licznerski and Professor of Internal Medicine and Neuroscience Elizabeth Jonas, researchers at the Yale School of Medicine have identified a leaky mitochondria as a novel downstream target of fragile X syndrome, a genetic disorder characterized by developmental delay, intellectual disability and autistic behaviors. In fragile X patients, mutations in the FMR1 gene lead to a loss of the protein FMRP that may cause a developmental mitochondrial leak to persist into adulthood. The leak allows cells to produce energy quickly but not efficiently, which is important during development but detrimental in adulthood. Jonas hypothesizes that this persistent leak in fragile X patients contributes to the immature structure of neurons and abnormally high levels of protein synthesis — leading to the symptoms associated with fragile X syndrome. 

“What I think is really fascinating is that it shows that the mitochondrial ATP synthase efficiency controls protein synthesis,” said Jonas, professor of internal medicine and neuroscience at school of medicine and senior author of this study. “Above and beyond all, that’s the thing that nobody in the entire fragile X field understands.”

Although fragile X syndrome is a widely researched disease, few have looked at the mitochondria in the context of the disorder. Often called the “powerhouse of the cell,” the mitochondria is a cell structure involved in energy production. Jonas only began studying the mitochondrial membrane after looking at intracellular membrane stores of calcium for neuronal function. She said about the discovery, “I didn’t even know what I was recording, but it turns out that I was recording mitochondria. It was just one of those really serendipitous things about science.”

This research focuses on a key part of the mitochondria called ATP synthase, an enzyme that produces ATP, a unit of energy for cells. Jonas’ team found that closing the ATP synthase leak channel in mice by injecting a drug called dexpramipexole leads to more mature neurons and decreased protein synthesis. In addition, fragile X-engineered mice who were injected with the drug showed a significant decrease in autistic-like behaviors such as excessive grooming and shredding of nests. With still no effective therapy or cure for fragile X patients, Dr. Jonas’ study reveals a promising path that can be explored for potential treatments.

“Interestingly enough, this drug has been used in humans already to treat ALS (amyotrophic lateral sclerosis),” said Dr. Paul Lombroso, professor emeritus in the Yale Child Study Center who has also conducted fragile X research. “A trial using dexpramipexole on fragile X patients could be started without jumping through all the regulatory hoops associated with testing new, unknown drugs.”

The researchers, however, stress that even though this study demonstrated positive effects, it is still possible that the drug will not work similarly in humans. Licznerski stressed that experiments carried out using mice do not always produce the same effects in human patients. Even so, pursuing this path is something that the researchers find worthwhile.

“Targeting this one leak channel is definitely a novel approach for treatment of fragile X, but we have to be careful,” said Licznerski. “But I am very excited about this. If it’s gonna work in humans, it is worth it to find out.”

Going forward, Jonas and her team hope to study how the channel actually functions and how it contributes to brain development. Expanding the body of knowledge of fragile X and mitochondrial function can be helpful not only for fragile X, but also for other disorders with disruption to ATP synthase.

According to the Center for Disease Control and Prevention, fragile X syndrome is the most common known cause of inherited intellectual disability.