Distinct Immune Protein Pattern Found in Rett Patients in Small Study

In people with Rett syndrome, cells known as fibroblasts have a distinct protein production profile — called a proteome — that overrepresents biological pathways related to immune function and inflammation, a small study reports.

These findings may help researchers better understand how abnormal inflammation manifests in Rett syndrome and affects different organs.

The study, “A proteomics approach to further highlight the altered inflammatory condition in Rett syndrome,” led by researchers in Italy, was published in the journal Archives of Biochemistry and Biophysics.

Rett syndrome is mainly caused by mutations in the MECP2 gene that result in a deficiency of the MECP2 protein, which is involved in the regulation of genes related to a variety of normal cell functions, particularly in the nerve cells of the brain.

Although the genetic basis of Rett syndrome has been identified, the disorder’s biological processes and how they relate to MECP2 deficiency are still being explored. Several factors are known to contribute to Rett syndrome’s complexity, including abnormal immune function and chronic low-level systemic inflammation.

Nuclear factor-kappa B (NF-κB), a protein that regulates immune responses, is associated with many disorders, including Rett syndrome. In a previous study, published in January 2020, the researchers demonstrated that fibroblasts — connective tissue cells — from Rett patients exhibited abnormal function of the NF-κB inflammatory signaling pathway.

Now, the same team of investigators analyzed differences in protein expression profiles in the fibroblasts of Rett patients and a control group.

Specifically, the study participants were two female patients diagnosed with classic Rett syndrome and MECP2 mutations and two healthy individuals. Consistent with previous research, protein production in patient-derived cells was distinctive from those of the healthy controls. 

Further analysis found 1,203 proteins expressed in cells from both Rett and the control group, as well as 289 unique to Rett, and 88 only in control cells. These results indicate that 19.37% of the total Rett proteome was unique compared with only 6.82% in controls.

The proteins that were differentially produced between the Rett and control group were associated with the regulation of immune responses and inflammation, including the NF-κB and tumor-necrosis factor (TNF) signaling pathways.

Of the 289 proteins unique to fibroblasts of Rett patients, 51 (17.65%) were associated with immune function and inflammation. Conversely, seven of the 88 (7.9%) control-distinct proteins were immune-related.

Cells from Rett patients showed a particular enrichment in proteins involved in the regulation of NF-κB activity. As such, the researchers assessed proteins unique to the Rett group that interact with a subunit of NF-κB known to have abnormal function in Rett. The analysis identified one interacting protein, sequestosome-1, that was diminished, and two proteins, catenin beta 1 and fibronectin, that were elevated in cells. Both catenin beta 1 and fibronectin are implicated in inflammation.

In the cells of Rett patients, the investigators also identified enriched pathways related to cellular stress, cell survival, and cell division, suggesting that these biological processes also may play a role in the disorder.

“Using an integrated proteomics strategy, we identified new proteins and biological processes that have changed due to MeCP2 deficiency and whose discovery can help to better understand the disease mechanisms underlying the chronic low-grade inflammation in [Rett],” the researchers wrote.

Among the limitations of the study, said the scientists, were the small number of samples analyzed.