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Discovery Reveals Fragile X Syndrome Begins Developing Even Before Birth

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Fragile X syndrome (FXS), the most common form of inherited intellectual disability, may be unfolding in brain cells even before birth, despite typically going undiagnosed until age 3 or later.

A new study published in the journal Neuron by researchers at the University of Wisconsin–Madison showed that FMRP, a protein deficient in individuals with fragile X syndrome, has a role in the function of mitochondria – a cell part that produces energy – during prenatal development. Their results fundamentally change how scientists understand the developmental origins of fragile X syndrome and suggest a potential treatment for brain cells damaged by the dysfunction.

The study was led by four postdoctoral fellows, Minjie Shen, Carissa Sirois, Yu (Kristy) Guo, and Meng Li, working in the lab of Xinyu Zhao, who is a neuroscience professor and neurodevelopmental diseases researcher at UW–Madison’s Waisman Center. The investigation found FMRP regulating a gene called RACK1 to promote mitochondrial function. Using a drug to enhance mitochondrial function, the researchers were able to rescue brain cells damaged by lack of FMRP.

Individuals with FXS may present developmental delays, such as not sitting, walking, or talking at expected ages, as well as mild to severe intellectual disability, learning disabilities, and social and behavioural problems. About half are also diagnosed with autism spectrum disorder.

In previous research, Zhao found that mitochondria in mice with an FMRP deficiency that imitates FXS were smaller and unhealthy. Diving deeper, they also discovered that FMRP regulates genes involved in mitochondria fission–fusion, a process during which mitochondria fuse into a bigger shape to produce more energy for the cell.

For the study, researchers grew neurons grown from induced pluripotent stem cells. Because the stem cells came from people with FXS, the researchers could study the development of the disorder at a cellular level, determining whether mitochondria in human cells experienced issues similar to those in mice.

“And indeed, we found that human neurons also have fragmented [smaller] mitochondria,” Zhao said. They also found fewer mitochondria in neurons derived from FXS patients, which they did not see in the neurons of the mice modelling FXS. “In human neurons, it’s a deficit in two-fold. Not just fission–fusion, but also likely in the production of mitochondria,” Zhao added.

Although it has long been known that FMRP is deeply involved in FXS, this new discovery pinpoints a role for the protein in early development of the condition.

Symptoms of FXS present long after the baby is born. Many babies appear to be developing typically before showing slower development, autistic features, or developmental deficits. Children with FXS are typically diagnosed at 3 years of age or older. “Which means many scientists have been thinking that FMRP is more important for the postnatal maturation state,” Zhao said.

FMRP is a protein that regulates the use of messenger RNA (mRNA), a sort of working copy of DNA used to produce the proteins that make things happen in cells. The researchers found that many mRNA strands that interact with FMRP are implicated in autism, providing a molecular link between FXS and autism spectrum disorder. Unexpectedly, many FMRP-bound mRNAs are expressed by genes classified as essential – genes that are very busy during prenatal development but less active after birth.

“This means that FMRP has a function in prenatal development that we have not really thought about before,” Zhao commented. “The fact that we found that FMRP also regulates prenatal development is really interesting and is actually indicating that what we see in fragile X syndrome, some of the effects already happened within the prenatal development.”

One of those essential genes is RACK1, identified for the first time as playing a role in FXS. “When RACK1 is lower in fragile X neurons, the mitochondria are suffering and the neurons exhibit mitochondrial deficit and hyperexcitability, like immature neurons. But when we reintroduce RACK1, we can rescue this,” Zhao said.

Using cultured neurons derived from individuals with FXS to screen for drugs, the researchers found a drug called leflunomide that corrected mitochondrial deficits. The treatment improved mitochondrial function and reduced the neurons’ hyperexcitability.

Next, Zhao wants to do a detailed biochemical analysis of mitochondrial dysfunction and figure out which key proteins are less present in FXS-affected neurons. She is also working on better understanding how RACK1 and leflunomide work to rescue mitochondrial function.

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