Defective Mitochondria Could Explain Neurological Impairment in Fragile X, Research Shows
Mutations in the FMR1 gene — the underlying cause of fragile X syndrome — result in mitochondria malformations inside developing brain nerve cells. Subsequently, this does not allow for neurons to create the necessary network of branches they need to communicate with other cells.
The study with that finding, “Reduced mitochondrial fusion and Huntingtin levels contribute to impaired dendritic maturation and behavioral deficits in Fmr1-mutant mice,” was published recently in the journal Nature Neuroscience.
Fragile X syndrome, the most common inherited cause of intellectual disability, is caused by mutations in the fragile X mental retardation (FMR1) gene located on the X chromosome. This results in failure to produce a protein called FMRP (fragile X mental retardation protein). However, how FMRP deficiency impairs brain function remains unclear.
Researchers at the University of Wisconsin-Madison had shown previously that FMRP plays an important role in neuron development (maturation). Now, they found that FMRP-deficient immature neurons cannot form normal dendrites, which are the projections neurons use to receive or transmit signals (information) from other nerve cells.
This occurs due to impaired function of small organelles inside neurons called mitochondria, the cells’ powerhouses. Neurons depend on mitochondria as an energy source to create the network of branches and contacts they need to communicate with other cells.
“Although mitochondria play a role in many diseases this is the first-time mitochondria dysfunction has been directly implicated in fragile X syndrome,” Xinyu Zhao, PhD, professor of neuroscience at the Waisman Center at the University of Wisconsin-Madison and study lead author, said in a press release.
Researchers first saw that mitochondria were fragmented in neurons that carried the FMR1 mutated gene (FMRP-deficient). “We see that the mitochondria are more fragmented, shorter and round rather than long and tubular, due either to decreased fusion or increased fission,” Zhao said.
They then transplanted neural progenitor cells, which have the capacity to differentiate into mature neurons, from fragile X patients or individuals without the disease into mice brains. Four months after transplantation, fragile X neurons showed not only impaired dendritic formation, but also increased oxidative stress, the outcome of poor mitochondria function.
Oxidative stress is caused by an imbalance between the body’s production of potentially harmful reactive oxygen species and its ability to contain them, promoting nerve cell damage.
“This is the first time that human fragile X neurons have been studied in any living brain,” Zhao added. “And so this information is more relevant to human neural development than what we can see in lab dishes.”
Using either a chemical, called M1, or a gene-editing technique (CRISPR-Cas9) to enhance mitochondria formation, researchers were able to rescue FMRP-deficient immature neurons, namely the formation of dendritic maturation.
Treating a mouse model of fragile X with M1 rescued animals’ behavioral abnormalities, including hyperactivity and impaired social interaction.
“When we restored mitochondria fusion with gene editing or a chemical compound, we partly restored neuronal development,” Zhao said. “In mice lacking FMRP, we also rescued some behavioral deficits using the chemical treatment.”
“This is the first direct evidence that mitochondrial dysfunction contributes to pathogenesis of fragile X,” she added, “and I hope it will open new investigations and new therapeutic developments.”
According to the authors, the major finding of this study “is that we have discovered the first convincing mechanism that could explain the neurological impairment in fragile X, and that mechanism is defective mitochondria,” Zhao said.
These findings shed light for potential ways to prevent or reverse loss of mitochondria function as potential therapies for fragile X that could be used after birth when neurons begin to mature.
Although targeting mitochondria as a potential therapy will take years to develop, the current findings are a big advance for neurodegenerative diseases that do not have an effective treatment.
“Human neuroscience seems to get more complex all the time, but I feel we’ve established a foothold that allows us to see the true source of difficulty in several serious neurological disorders. And that’s exactly our role as basic neuroscientists,” Zhao added.
These findings also may carry significance to other diseases like autism. In fact, fragile X is the most common genetic cause for autism. “Autism is linked to more than 1,000 genes,” Zhao said. “Because the fragile X gene is linked to more cases of autism than any other gene, what we have learned from fragile X helps us to understand autism.”