Researchers reveal underlying genetic pathway behind neurological dysfunction in Rett syndrome

Medical researchers led by Kyushu University have revealed a possible underlying genetic pathway behind the neurological dysfunction of Rett syndrome. The team found that deficiencies in key genes involved in pathology cause neural stem cells to generate fewer neurons by producing more astrocytes – the maintenance cells of the brain.

The researchers hope that the molecular pathology they identified, as reported in the journal Cell reports, may lead to potential therapeutic targets for Rett syndrome in the future.

Rett syndrome is a progressive neurodevelopmental disorder characterized by impaired cognition and coordination – with varying severity – and occurs in approximately one in 10,000 to 15,000 women. However, it is difficult to identify initially because children seem to develop normally during the first 6 to 18 months.

Rett syndrome is caused by mutations in a single gene called methyl-CpG 2 binding protein, or MeCP2. The gene was identified over two decades ago and much has been discovered since, but exactly how mutations cause the pathology remains elusive. “

Hideyuki Nakashima, first author, Kyushu University Faculty of Medical Sciences

In their previous research, the team had identified that MeCP2 acts as a regulator for the processing of specific microRNAs to control the functions of neurons. They therefore returned to find out whether this pathway was also involved in the differentiation of neural stem cells.

Compared to messenger RNA, the final template transcribed from DNA that is used by a cell to synthesize proteins, microRNAs – or miRNAs – are much smaller and act to regulate messenger RNA for itself. ensure that the cell is producing the correct amount of protein.

“Through our investigation, we found several microRNAs associated with MeCP2, but only one affected neural stem cell differentiation: a microRNA called miR-199a,” explains Nakashima. “In fact, when MeCP2 or miR-199a are disrupted, we have found that it increases the production of cells called astrocytes.”

Astrocytes are like the supporting cells in your brain. While the neurons trigger the electrical signals, the astrocytes are there to help keep everything else going. During development, astrocytes and neurons are generated from the same type of stem cells, called neural stem cells, where their production is carefully controlled. However, dysfunction of MeCP2 or miR-199a causes these stem cells to produce more astrocytes than neurons.

“Further analysis showed that miR-199a targets the Smad1 protein, a transcription factor essential for proper cell development. Smad1 works downstream of a pathway called BMP signaling, which is known to inhibit the production of neurons and facilitate the generation of astrocytes, ”says Nakashima.

To further the process, the team established a brain organoid culture – a 3D culture of neural stem cells that can mimic aspects of brain development – from iPS cells derived from patients with Rett syndrome. When they inhibited BMP, short for bone morphogenetic protein, the team was able to reduce the abnormal differentiation of neural stem cells.

“Our results have given us valuable insight into the role of MeCP2, miR-199a and BMP signaling in the pathology of Rett syndrome,” concludes Kinichi Nakashima, who led the team. “Further investigation is needed, but we hope this can lead to clinical treatments for the symptoms of Rett syndrome.”