Author: Sean Krivitsky, Class of 2026

Rett syndrome (RTT) is a severe neurological disorder found primarily in females that causes impairment in essential functions including breathing, eating, and walking abilities. The disorder is characterized by slowed brain growth, which can lead to various mental and physical disabilities. Key markers and causes of RTT are mutations on a gene called MECP2. MECP2 is an X-linked gene that plays an important role in the functioning of the brain, particularly through the regulation of neurons. Current research indicates that its role is primarily supporting the maintenance of synapses, which allow communication between neurons, suggesting that it is crucial for proper functioning of the brain.

Recent research led by Jialin Sun of the Ballas lab at Stony Brook University investigated the impact of mutations in the MECP2 gene on the properties of a certain type of glial cells known as astrocytes. Astrocytes perform important homeostatic and metabolic functions to support neurons and their surrounding environment. In RTT, the role of astrocytes in overall brain bioenergetics is impaired by mutations in MECP2. By inserting RTT-associated mutations into human embryonic stem cells, the Ballas lab generated a model for RTT with which they tested the effects of RTT on gene regulation and tracked markers of key astrocyte functions. Mutated astrocytes exhibit decreased levels of ATP and other markers of energy metabolism, and increased signs of anaerobic respiration. Astrocytes have also been known to play an important role in maintaining the homeostasis of neurotransmitters such as the excitatory neurotransmitter called glutamate. Mutant astrocytes were found to improperly uptake glutamate, which helps to explain the excitatory imbalance common in RTT patients that results in seizures. Furthermore, deficiencies in mutant astrocyte mitochondrial function were also identified, resulting in elevated levels of oxidative damage and stress along with irregularities in their cell cycle.

These findings made by the Ballas lab at SBU provide much-needed insights into this rare and relatively poorly understood disorder. This research reveals important aspects of the pathological mechanism underlying Rett syndrome and its development. Furthermore, these findings pave the way for the identification of biomarkers to better understand and diagnose the disorder, while also opening up new avenues for potential therapeutic interventions for this severe neurological disorder.

Figure 1. Young girl with Rett syndrome displaying clasping behavior characteristic of the disorder.

Works Cited

[1] Sun, J., Sivan Osenberg, Irwin, A., Ma, L.-H., Lee, N., Xiang, Y., Li, F., Wan, Y.-W., Park, I.-H., Mirjana Maletic-Savatic, & Ballas, N. (2023). Mutations in the transcriptional regulator MeCP2 severely impact key cellular and molecular signatures of human astrocytes during maturation. Cell Reports, 42(1), 111942–111942. https://doi.org/10.1016/j.celrep.2022.111942

[2] Image retrieved from: https://commons.wikimedia.org/wiki/File:Rett_girl_with_stereotyped_hands_movements.jpg