New molecular insights into the early stages of Rett syndrome

Scientists studying the severe developmental disorder known as Rett syndrome have discovered a series of important molecular changes that occur long before symptoms appear. The findings could be used to develop better treatments for this devastating and life-shortening condition, the researchers said.

Rett syndrome almost exclusively affects girls. Children with Rett disease initially appear healthy and develop normally for the first 6 to 18 months before they begin to regress and lose previously acquired skills. For example, a child who used to crawl may no longer be able to crawl or his or her language skills may decline. Other symptoms of Rett include eating disorders, seizures, “dangling” limbs, and repetitive hand movements that are characteristic of the disease. These symptoms can range from mild to severe. Life expectancy varies, but most people with Rett die by their 40s or 50s.

New insight into the early symptoms of the disease comes from Dr. Sameer Bajkar, who recently joined the University of Virginia School of Medicine. While doing his postdoctoral research (at Baylor College of Medicine and UVA), Bazikar and his collaborators began investigating how mutations in certain genes occur. MECP2causing the development of rets.

The study uncovered an entire “cascade” of molecular changes that fundamentally alter how genes work in brain cells. In particular, scientists found that this cascade causes widespread “circuit-level” problems in the hippocampus, a region of the brain essential for memory and learning. As a result of these sweeping changes, Bazikar and his colleagues determined that brain cells called neurons begin to malfunction.

We artificially triggered the onset of Rett syndrome symptoms in mice and precisely mapped the sequence of events that occur. MECP2 It's out of order. Our research has uncovered a core set of genes that are disrupted very early on, before any obvious symptoms appear. These genes may downstream cause Rett syndrome symptoms. MECP2 Its expression level may also be important for normal brain function. ”

Dr. Sameer Bajikar, UVA Department of Cell Biology and Biomedical Engineering

A better treatment for Rett syndrome

The discovery of these molecular changes and the specific mechanisms involved in them has shed much-needed light on the development of Rett syndrome. It also sets the stage for new and better ways to treat this condition. For example, there is great excitement about the possibility of: gene therapy restore MECP2 Gene function in Rhett's children. The challenge, however, is that increasing the gene's activity too much can prove toxic to brain cells.

Doctors need a way to monitor gene activity, and Bazikar's research may finally provide that. For example, doctors may be able to monitor biological markers, or “biomarkers,” that scientists have identified. MECP2 Genes are functioning at appropriate levels.

More research is needed to translate this discovery into treatments, but Bajkar is excited about the potential of his discovery.

“We have discovered several candidate biomarkers that are sensitive to: MECP2 “The potential key to developing safe gene therapies for Rett points to the importance of cataloging and understanding the earliest biological events that occur during the onset of symptoms in neurodevelopmental disorders more broadly. ” he said.

Publication of survey results

The researchers published their findings in a scientific journal neuron. The research team includes: Bajikar, Jian Zhou, Ryan O'Hara, Harini P. Tirumala, Mark A. Durham, Alexander J. Trostle, Michelle Dias, Yingyao Shao, Hu Chen, Wei Wang, Hari K. Yalamanchili, and Ying-Woi. Configured. Wang, Laura A. Banazinski, Zandong Liu, and Huda Y. Zogbi. Mr. Bajkar has no financial interest in the work. A list of author disclosures is included in the paper.

This research was supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development of the National Institutes of Health, grants F32HD100048, R01HD109239 and U54HD083092. National Institute of Neurological Disorders and Stroke, grants R01NS057819 and K99/R00NS129963. National Institute of General Medical Sciences, grant R35GM124958. Welch Foundation, Grant I-2025. American Cancer Society, Grant 134230-RSG-20-043-01-DMC. Recipient of the NRI Zoghbi Scholar Award through Texas Children's Hospital. International Rett Syndrome Foundation, Grant 4013. and the Howard Hughes Medical Institute.

UVA's School of Biomedical Engineering is a joint program between the School of Medicine and UVA's College of Engineering and Applied Sciences.