Early Protein Alterations May Drive the Development of Rett Biomarkers

Joana Carvalho, PhD avatar

by Joana Carvalho, PhD |

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Understanding protein alterations during the early phases of neuronal development may open the door to the development of new biomarkers and therapeutic strategies for Rett syndrome, a study says.

The finding, “Quantitative proteomic alterations of human iPSC-based neuronal development indicate early onset of Rett syndrome,” was published in bioRxiv, a preprint biology platform.

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

“[However,] the mechanisms by which impaired MeCP2 induces the pathological abnormalities in the brain [of patients with Rett syndrome] is not understood,” the investigators wrote.

In this study, a team of Dutch researchers set out to investigate the molecular mechanisms involved in the onset of Rett syndrome To do so, they used neuronal stem cells (NSCs) derived from patients’ induced pluripotent stem cells (iPSCs), and applied high-resolution quantitative mass-spectrometry analysis during the first stages of neurons’ development.

Neuronal stem cells are stem cells that can grow into any type of nerve cell in the body. 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. Mass-spectrometry is an analytical technique that allows the separation and sorting of molecules by their mass (weight).

Mass-spectrometry analysis revealed that even before the first symptoms of the disease became apparent, there were significant alterations in the structure of proteins involved during neuronal development in NSCs derived from patients’ iPSCs and control cell lines — cells that were genetically manipulated to reflect the features of Rett syndrome.

In addition, the team found these alterations became more obvious as NSCs progressed through their neuronal differentiation program, although changes in proteins involved in the body’s immune response, metabolism and calcium signaling cascades were already affected during the early stages of development.

“[T]his indicates that next to dysregulation in neurodevelopmental processes, disease mechanisms underlying RTT phenotypes [symptoms of Rett syndrome] could also involve immunity, calcium signaling and metabolism,” the researchers wrote.

“Overall, we show that dysregulation of MeCP2 affects protein expression changes associated with neurodevelopmental functions at early stages of neuronal differentiation. The finding, that neuronal stem cells of RTT [Rett syndrome] patients do show altered protein expressions responsible for neuronal development and maturation, indicates that RTT influences the patients much earlier than first symptoms actually appear,” they added.

“Therefore, we hope that our results give awareness of the early pre-natal onset of RTT and emphasize the need of early testing followed by an effective treatment,” they concluded.