Misregulation in NPCs’ Development Might be Implicated in Rett Syndrome, Study Says

Proteomic analysis — the characterization of all the proteins present in a cell at a given time — has revealed that a misregulation in the development of neural progenitor cells (NPCs), which eventually give rise to different types of nerve cells, might be implicated in Rett syndrome.

The study, “Proteomic analyses reveal misregulation of LIN28 expression and delayed timing of glial differentiation in human iPS cells with MECP2 loss-of-function,” was published in PLOS One.

Rett syndrome is a rare genetic disorder characterized by developmental and intellectual disabilities. It mostly affects girls. Rett patients typically have severe learning, communication and motor coordination impairments. The condition is caused by mutations in the MECP2 gene, which provides instructions to make a protein called MeCP2, involved in maintaining synapses — the junctions between two nerve cells that allow them to communicate.

Previous studies have shown that MECP2 mutations in boys lead to congenital encephalopathy (loss of brain function), neurodevelopmental arrest, and premature death during the first years of life. “However, how MECP2 mutations affect [nerve cells’] development is not well-understood,” the researchers said.

In this study, a team of researchers from the University of California San Diego and collaborators set out to characterize the earliest stages of the disease from a biological standpoint using induced-pluripotent stem cells (iPSCs) from two boys carrying MECP2 mutations and their unaffected fathers (controls). iPSCs are fully matured cells that are reprogrammed back to a stem cell state, where they are able to grow into almost any type of cell.

To investigate potential perturbations during the earliest stages of nerve cells’ development, researchers differentiated iPSCs collected from boys and their fathers into neural progenitor cells. Results showed that neural progenitor cells derived from the boys were unable to grow into astrocytes (non-neuronal cells responsible for supporting and protecting neurons) when cultured in a lab dish.

Further proteomic analysis revealed that neural progenitor cells derived from both boys also contained excessive amounts of the protein LIN28 — an important regulator of nerve cell fate and developmental timing — compared to healthy neural progenitor cells derived from their fathers.

In addition, researchers found that the excessive production of LIN28 in neural progenitor cells derived from patients’ iPSCs not only prevented astrocytes’ differentiation, but also impaired the formation of synapses. Investigators managed to partly revert this effect by reducing the levels of LIN28 in mutant neural progenitor cells through a technique called genetic silencing (using short hairpin RNA delivery).

“Our unbiased, discovery-based proteomic approach identified a molecular change in male [Rett syndrome] patient [neural progenitor cells] that may contribute to the astrocytic and neuronal deficits that are observed in subsequent terminally differentiated cultures, and demonstrate the value of proteomic analyses in providing mechanistic insights underlying disease progression,” researchers concluded.