Recent technological advancements such as high-throughput genome sequencing and functional magnetic resonance imaging (fMRI) have allowed researchers to discover more about the human body and its inner biological secrets than ever before. Scientists are now able to uncover the sequences of entire genomes for almost any organism on the planet.
These advancements have allowed the scientific community to understand how neurons are responsible for our brain’s actions. While scientists are just at the frontier of discovering the true mechanisms that allow us to perceive the world as we do, the discoveries we have made are setting us up to potentially treat or cure diseases that affect millions.
Xinyu Zhao, a professor of neuroscience and Waisman Center Investigator, and her team of scientists at UW-Madison are using such technologies in an attempt to solve Fragile X syndrome (FXS), one of the most common hereditary cognitive impairment disorders. This disorder is caused by a genetic mutation on the X chromosome and approximately a third of the victims develop autism. People with this mutation exhibit cognitive disorder that ranges from mild learning disabilities to severe mental impairment. It is estimated that over 20 million people worldwide are affected by FXS.
Zhao and her team recently showed that the proteins lost in fragile X, named FMRP and its related FXR2P, play an important role in the proper generation and development of neurons from stem cells in the brain. Zhao’s research published in the journal Cell Reports showed the involvement of these proteins as not only regulators for proper neural development that are responsible for memory formation and learning, but also that they can have an additive effect through the same molecular pathway. Importantly, both of these proteins are at the center of the autism protein network.
Zhao first looked at this relationship in mouse models. “When we took a look at mice that don’t have either and those that have both, we found that the Fragile X and autism-related proteins both regulate the same target gene. The mice that were missing both had very severe cognitive impairment,” said Zhao. Both FMRP and FXR2P are important for proper neuronal maturation. The neurons lacking both proteins exhibited more severe developmental defects than neurons lacking one of them or neurons present with both of them.
“We had an initial hypothesis that these proteins were connected in the regulation of neuronal development. Autism [and FXS] occurs due to the improper neuronal maturation at the final stages when [new neurons] form connections with other neurons,” said Zhao. After looking at these proteins and performing extensive molecular analyses, they discovered a common downstream target of these two proteins, a neurotransmitter receptor. The lack of both of these two proteins leads to more profound functional loss of this receptor, which is responsible for defective neuronal development.
Zhao is currently working with human stem cells with defects in the Fragile X gene to see if they exhibit a similar differentiation and maturation deficit as mouse cells.
In most FXS patients, the loss of FMRP protein is due to gene inactivation, which we cannot model in mouse cells. These human stem cells provide an indispensable model to understand FXS and develop potential therapies. “We are currently in the early stages of these experiments because human cells are trickier to work with and take longer to differentiate in neurons than those of mouse cells. Our goal is to test what happens if the FMR2P gene is taken away in these human cells. If we are able to find a way to reactivate this gene, we could potentially find a cure to Fragile X syndrome,” said Zhao.
If scientists can restore the gene function that is inactive in FXS patients, new neurogenesis can occur, restoring normal learning and memory. While a cure for FXS is decades away, future technological developments may allow for breakthroughs in the neuroscience field.