Loss of MECP2, the defective protein in most people with Rett syndrome, induces premature growth arrest of bone marrow stem cells — known as senescence — and limits their energy production, according to a mouse study.
These biological alterations may underlie the development of the disease, the researchers said.
Over 90% of Rett syndrome cases are caused by mutations in the MECP2 gene, resulting in a shortage of methyl-CpG binding protein 2 (MECP2).
This protein works as a regulator that can drive either the activation or silencing of genes, by changing chromatin — the DNA-protein complex that packages DNA into chromosomes inside a cell nucleus.
“For this reason, some researchers identify [Rett syndrome], which is caused by mutations in the MECP2 gene, as ‘a paradigmatic example of a chromatin disorder,'” the researchers said.
MECP2 is present in cells throughout the body, but is particularly abundant in the brain, where it is likely involved in the maintenance of the connections called synapses, between nerve cells.
As a chromatin modulator which can regulate the activity of multiple genes, MECP2 can play a key role in the functioning of stem cells. These are cells that can divide and renew themselves for long periods, and are capable of giving rise to almost any cell type in the body.
These cells are crucial not only during early development. They also serve as a sort of internal repair system, forming pools of cells that divide nearly endlessly to replenish other dying cells throughout a person’s life.
In a prior study, the researchers showed that mesenchymal stromal cells (MSCs) taken from the bone marrow of Rett patients were prone to senescence — a state of permanent growth arrest without involving cell death, as a result of the accumulation of detrimental changes over time. Senescence also has been linked to the decline in cellular function underlying aging.
MSCs, also known as bone marrow stromal stem cells, are a multipotent group of bone marrow cells able to form bone, cartilage and stromal cells, which support blood formation, fat, and fibrous tissue.
The team recently also found that mouse neural stem cells (those that give origin to neurons) deficient for MECP2 also are affected by premature senescence.
To better understand the role played by MECP2 in triggering the senescence of stem cells, the researchers isolated MSCs from the bone marrow of a Rett mouse model, and from healthy mice, and compared their biology, including differences in metabolism.
They explored not only metabolic changes that are particularly relevant for senescence, but also the impact of MECP2 deficiency in MSCs, “given their important role in supporting hematopoiesis [blood cell formation] and contributing to homeostasis of several organs and tissues.”
As progenitors, or the originators of bone cells, understanding MSC biology “could be of interest, since it has been reported that [Rett] patients develop several skeletal abnormalities, such as low bone density, high frequency of fractures, and scoliosis,” the investigators added.
MSCs from Rett mice proliferated less and were more susceptible to senescence compared with those from healthy mice. One of the evident signs of senescence was the lower capacity of these cells to repair DNA damage.
Importantly, although MSCs from Rett mice were able to adapt their energy needs to the availability of nutrients (metabolic flexibility) to the same degree that healthy cells did, they had more problems producing energy.
Specifically, they had a weaker capacity to produce ATP — the primary “exchange coin” used by cells to store energy and use it to power reactions — inside mitochondria, which are the ‘power houses’ of cells. This occurred as the mitochondria partially lost the ability to respond to an increase in ATP need.
Interestingly, MSCs from Rett mice could cope with a higher demand of energy if, instead of being fed with sugar (glucose), they were fed with palmitate, a common fatty acid naturally found in the body. This result agrees with findings that showed that people with Rett may benefit from a ketogenic diet, which is based mainly on lipid (fat) supplementation.
“The proper functioning of stem cell compartments is of great importance, since it is involved in regulating the balance between quiescence [inactivity], proliferation, and differentiation,” the researchers said.
When senescence occurs in these cells, the body can run out of stem cells and become unable to properly renew tissues.
“Our results support the idea that an alteration in mitochondria metabolic functions could play an important role in the pathogenesis [disease mechanism] of [Rett],” the researchers concluded.