Genetic pathway behind neurological disorder in Rett syndrome

Sneha Singhal, Jaypee Institute of information technology, Noida

What is the Rett Syndrome?

Rett syndrome also called RTT, is a rarely occurring genetic neurological or brain disorder. As a developmental disorder, it is found mostly in girls. There are severe functional impairments associated with Rett syndrome, affecting nearly every aspect of the child’s life. Language impairment and poor coordination are among the symptoms of this disorder. In affected individuals, growth is often slowed, walking is difficult and head size is smaller. There are approximately one to five females born with Rett syndrome every 10,000 to 15,000 births. It is difficult to detect initially as the first six-18 months of a child’s life seem normal. Mutations of just one gene, called methyl-CpG binding protein 2, cause Rett syndrome. Over two decades ago, the gene was discovered, but it is still unclear how specific mutations result in the pathologies.

A possible genetic pathway behind Rett Syndrome:

A possible underlying genetic pathway has been revealed behind the neurological dysfunction of Rett syndrome by medical researchers. They found that genetic deficiencies lead to neural stem cells producing more astrocytes–brain maintenance cells–instead of neurons, which results in less neurogenesis. As reported in the journal Cell Reports, researchers hope to identify molecular targets for treating Rett syndrome with their discoveries. In previous studies, it was shown that MeCP2 functions as a regulator of microRNA processing in neurons. So, they investigated whether this pathway also plays a role in neural stem cell differentiation. MicroRNAs–or miRNAs–are much smaller than messenger RNA, the final template transcribed from DNA and used by the cell for protein synthesis. By ensuring the cell makes the correct amount of the desired protein, they regulate messenger RNA.

Nakashima explained that a microRNA called miR-199a affects the differentiation of neural stem cells through the investigation of MeCP2. They found that MeCP2 or miR-199a disruptions increased the production of astrocyte cells. Astrocytes act as brain supporting cells. These cells are the ones who maintain everything else in the body while neurons send electrical signals. From neural stem cells, astrocytes and neurons develop. Each stage of development is regulated differently. However, when there is an imbalance in MeCP2 or miR-199a, this stem cell tends to produce more astrocytes than neurons.

Furthermore, miR-199a appears to target the transcription factor Smad1, a key regulator of cellular development. Nakashima stated that a pathway known as BMP signaling inhibits the formation of neurons and facilitates the development of astrocytes in the presence of Smad1. The process was examined further by creating a brain organoid culture from induced pluripotent stem (iPS) cells derived from patients with Rett syndrome. It was a 3D culture of neural stem cells mimicking the development of the brain. The team was able to reduce abnormal neural stem cell differentiation by inhibiting BMP, or bone morphogenetic protein.

Conclusion:

In conclusion, Kinichi Nakashima, who headed the research team, says that the findings have provided us with valuable insight into MeCP2, miR-199a, and BMP signaling in Rett syndrome pathology. They hope that this will ultimately lead to clinical treatments for the symptoms of Rett syndrome. miR-199a decreases Smad1 protein levels, which is closely related to BMP signaling. BMP inhibitors are effective in halting Rett patient-derived brain organoid development.

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References:

1. Henderson, E. B. (2021, July 3). Researchers reveal underlying genetic pathway behind neurological dysfunction of Rett syndrome. News-Medical.Net. https://www.news-medical.net/news/20210702/Researchers-reveal-underlying-genetic-pathway-behind-neurological-dysfunction-of-Rett-syndrome.aspx
2. Nakashima, H., Tsujimura, K., Irie, K., Imamura, T., Trujillo, C. A., Ishizu, M., Uesaka, M., Pan, M., Noguchi, H., Okada, K., Aoyagi, K., Andoh-Noda, T., Okano, H., Muotri, A. R., & Nakashima, K. (2021). MeCP2 controls neural stem cell fate specification through miR-199a-mediated inhibition of BMP-Smad signaling. Cell Reports, 35(7), 109124. https://doi.org/10.1016/j.celrep.2021.109124

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