New Insights into the Prenatal Development of Fragile X Syndrome
Recent research has upended previous understandings of Fragile X syndrome by revealing its potential prenatal origins. Scientists have shed light on the pivotal role of the FMRP protein and introduced a potential treatment to mitigate the impact of this syndrome on brain cells.
A Paradigm Shift in Understanding Fragile X Syndrome
Fragile X syndrome, the most prevalent form of inherited intellectual disability, might start affecting brain cells even before birth, contrary to the traditional belief that it remains undiagnosed until age 3 or later.
A groundbreaking study published in the Neuron journal on October 10, conducted by researchers at the University of Wisconsin–Madison, has uncovered a significant breakthrough. This research suggests that FMRP, a protein deficient in individuals with Fragile X syndrome, plays a crucial role in mitochondrial function during prenatal development. This discovery fundamentally transforms our comprehension of how Fragile X syndrome originates and opens the door to potential treatments for brain cells affected by this dysfunction.
The Central Role of FMRP and Its Implications
The study, led by four postdoctoral fellows—Minjie Shen, Carissa Sirois, Yu (Kristy) Guo, and Meng Li—working in the lab of Xinyu Zhao, a neuroscience professor and neurodevelopmental diseases researcher at UW–Madison’s Waisman Center, revealed that FMRP regulates a gene called RACK1, thereby promoting mitochondrial function. By using a drug to enhance mitochondrial function, they successfully rescued brain cells damaged due to the lack of FMRP.
Individuals with Fragile X syndrome often exhibit developmental delays, including delayed sitting, walking, or speaking, alongside varying degrees of intellectual disability, learning difficulties, and social and behavioral challenges. Approximately half of those affected also receive a diagnosis of autism spectrum disorder.
In prior research, Zhao and her team discovered that mice with an FMRP deficiency, mimicking Fragile X syndrome, had smaller and unhealthy mitochondria. Going further, they identified that FMRP regulates genes associated with mitochondrial fission-fusion—a process in which mitochondria merge to produce more energy for the cell.
From Mice to Human Neurons: A Comparative Analysis
For their study, researchers grew neurons from induced pluripotent stem cells, which were derived from individuals with Fragile X syndrome. This allowed them to investigate the disorder’s cellular development and assess whether human cells experienced mitochondrial issues similar to those observed in mice.
Surprisingly, the researchers found that human neurons also exhibited fragmented (smaller) mitochondria, and there were fewer mitochondria in neurons derived from Fragile X syndrome patients—a phenomenon not observed in the mice used to model the syndrome.
“This means that FMRP has a function in prenatal development that we have not really thought about before,” Zhao explained. “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.”
Uncovering the Link Between FMRP, Fragile X Syndrome, and Autism
FMRP is a protein that regulates the use of messenger RNA, acting as a working copy of DNA for protein production in cells. The researchers discovered that many of the mRNA strands interacting with FMRP are linked to autism. This provides a molecular connection between Fragile X syndrome and autism spectrum disorder. Interestingly, many FMRP-bound mRNAs originate from essential genes—genes that play a significant role during prenatal development but become less active after birth.
The findings suggest that FMRP plays a critical role not only in postnatal development but also in prenatal development, challenging previous assumptions.
A Glimpse into Potential Treatments and Future Research
One of these essential genes is RACK1, identified for the first time as playing a role in Fragile X syndrome.
“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 stated.
Using cultured neurons from individuals with Fragile X syndrome to screen for drugs, the researchers identified leflunomide as a potential treatment that corrected mitochondrial deficits. This treatment not only improved mitochondrial function but also reduced hyperexcitability in neurons.
Zhao’s next steps involve conducting a detailed biochemical analysis of mitochondrial dysfunction and unraveling the mechanisms by which RACK1 and leflunomide work to restore mitochondrial function.
This research, with contributions from various collaborators at the Waisman Center and supported by grants from the National Institutes of Health and the Department of Defense, marks a significant leap in understanding Fragile X syndrome and offers hope for potential treatments that could impact the lives of those affected by this condition.
Table of Contents
Frequently Asked Questions (FAQs) about Prenatal Origins of Fragile X Syndrome
What is Fragile X syndrome?
Fragile X syndrome is the most common form of inherited intellectual disability, characterized by developmental delays, intellectual challenges, and various social and behavioral issues. It often goes undiagnosed until the age of 3 or later.
What did the research reveal about Fragile X syndrome’s developmental origins?
Recent research has uncovered that Fragile X syndrome may begin affecting brain cells even before birth, contrary to earlier beliefs. The study identified a critical role for the FMRP protein in regulating mitochondrial function during prenatal development.
How does the FMRP protein contribute to the development of Fragile X syndrome?
The FMRP protein was found to regulate a gene called RACK1, promoting mitochondrial function. In cases where FMRP is deficient, brain cells suffer from mitochondrial dysfunction. However, the study showed that enhancing mitochondrial function with a drug could rescue these damaged cells.
What is the connection between Fragile X syndrome and autism?
The research unveiled a molecular link between Fragile X syndrome and autism spectrum disorder. Many of the mRNA strands that interact with FMRP are implicated in autism. Surprisingly, these mRNA strands are primarily associated with essential genes that play a significant role during prenatal development.
What are the implications of these findings for prenatal development?
The findings suggest that FMRP not only plays a crucial role in postnatal development but also in prenatal development. This discovery challenges previous assumptions about the timing of FMRP’s involvement in Fragile X syndrome.
Is there a potential treatment on the horizon for Fragile X syndrome?
Yes, the study identified a drug called leflunomide that corrected mitochondrial deficits in neurons derived from individuals with Fragile X syndrome. This treatment improved mitochondrial function and reduced hyperexcitability in these neurons.
What are the future research directions in this field?
Future research aims to conduct a detailed biochemical analysis of mitochondrial dysfunction and investigate the mechanisms by which RACK1 and leflunomide work to restore mitochondrial function. This research holds promise for advancing our understanding of Fragile X syndrome and potential treatments.
More about Prenatal Origins of Fragile X Syndrome
- Neuron Journal Article
- University of Wisconsin–Madison News Release
- Waisman Center at UW–Madison
- National Institutes of Health
- Department of Defense
