Lab study findings on MECP2 offer clues for better understanding Rett
Researchers find gene mutations cause problems in how nerve cells work
Mutations in the MECP2 gene — which typically underlie Rett syndrome — cause problems in how neurons, or nerve cells, produce energy and communicate, and affect how well they can repair breaks to DNA.
That’s according to the findings of a new study, done in both human brain cells and rat models of the rare genetic disease, which researchers say offer clues for understanding how Rett syndrome develops.
These data can help identify which mechanisms could “serve as proxies for experimentally targeting and developing therapeutic strategies,” the scientists wrote, noting that “this study is the first to profile and compare human and rat models of [Rett].”
The study, “Evidence for neuronal DNA damage in Rett Patient Brain,” was published in the journal Disease Models & Mechanisms.
Rett syndrome is most often caused by mutations in MECP2, a gene that provides the instructions needed to produce a protein of the same name that’s key for normal brain development. A shortage of the MeCP2 protein interferes with how nerve cells function, causing an array of symptoms.
MECP2 mutations shown to affect multiple systems in Rett patients
Early in infancy, children with Rett syndrome may develop normally, but later, they begin to lose some of the skills they had learned — a process called developmental regression.
Because Rett syndrome is X-linked, males — having only one X chromosome —with MECP2 mutations rarely survive to birth. In females, random X-chromosome inactivation produces a mosaic brain in which some brain cells express the normal MECP2 gene while others express the nonfunctional variant. This variation in gene expression complicates efforts to study the mechanisms of the disease.
To get around this challenge, a research team from the University of California, Los Angeles, examined the transcriptional profile — the pattern of genes being turned on or off — of single nerve cells. This allowed the researchers to compare those that produce a functional MeCP2 protein with those that have little or no functional protein.
Using nerve cells from postmortem brain samples of five girls with Rett syndrome, the researchers found that those without functional MeCP2 had changes in genes related to synaptic function. That refers to how nerve cells connect and send signals, or how they produce and use energy, as well as to metabolism and DNA repair.
Rat model can be used for testing possible treatments, researchers say
Previous studies have shown that nerve cells lacking functional MeCP2 exhibit increased features of senescence, a state in which cells cease dividing and functioning normally. To investigate whether this occurs in Rett, the researchers measured the expression of GLB1, a senescence-associated gene, and found it to be elevated in nerve cells with reduced MECP2. These cells also displayed evidence of DNA strand breaks.
In rats in which the MECP2 gene was completely removed, the results were very similar to those observed in nerve cells from patients. This means these rats can be a useful in vivo model — meaning a living system — to study Rett syndrome and test possible treatment candidates.
With this novel profiling approach, we found that mutant [nerve cells] from the brains of patients with Rett syndrome show patterns of defects.
Overall, the study’s findings point to changes in multiple systems in Rett syndrome. According to the team, such changes were found not just in communication between nerve cells, but also in how neurons produce energy and how well they can repair breaks in DNA as a way to prevent senescence.
“With this novel profiling approach, we found that mutant neurons from the brains of patients with Rett syndrome show patterns of defects,” the researchers wrote. “Together, these data highlight potentially defective molecular, physiological and metabolic pathways in brain neurons of patients with Rett.”
These results — identifying changes that occur in the human brain in people with Rett syndrome — “is critical to understand the etiology [the reasons behind the cause] of the disease,” the scientists wrote.
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