Study Links Fragile X Syndrome and Mitochondria Dysfunction

Fragile X syndrome is an X-linked neurological disorder; patients with the syndrome have difficulty in learning and language, hyperactivity, and extreme sensitivity to light and sound. Previous studies have revealed that the syndrome is caused by the loss of an RNA-binding protein called FMRP, but how this loss causes the effects observed in fragile X syndrome was unknown until now. A study published recently in Nature Neuroscience reveals the mechanism by which a single mutation causes the effects seen in fragile X.

The new study was done by scientists at the Waisman Center at the University of Wisconsin-Madison. Their findings revealed that the fragile X gene fails to produce its unique protein when mutated, resulting in malformation of mitochondria in developing neurons. This causes the neuron to be unable to create the necessary network of branches and connections needed to communicate, causing intellectual deficits.

According to the authors, this is the first time mitochondria dysfunction has been linked to fragile X. These findings add to growing evidence of mitochondria’s important role in brain development. Healthy mitochondria allow neurons to create more energy, have greater electrical activity, and support establishment of cells essential to brain function. Other developmental disorders, such as Huntington’s, Rett syndrome, and Down syndrome also appear to feature mitochondria dysfunction.

When a chemical that promotes mitochondrial formation was administered to mice transplanted with human fragile X cells, behaviors like hyperactivity and impaired social interaction were reversed in the animals. These results further demonstrate the results obtained in the previous studies and also provide a glimpse into the potential to use these findings as a jumping off point for disease treatment.

Fragile X syndrome is also linked to autism, with approximately 2 to 3% of people with autism also having fragile X. Because these two disorders are genetically linked, the findings from this study could also have implications in understanding and treating autism.

Image: Microscope images from the lab of Xinyu Zhao compare neurons with normal or mutated fragile X gene. With the mutation, mitochondria were shorter and failed to join together. A loss of fusion impairs the neuron's ability to communicate and plays a role in causing fragile X symptoms. Scale bar shows 10 microns. Image courtesy of Zhao lab, Waisman Center, University of Wisconsin-Madison.