The neurodevelomental disease Rett syndrome is usually caused by mutations in a gene called MECP2, which is located on the X chromosome. Patients lose coordination, mobility, and their ability to speak and use their hands, among other issues. Scientists have now found that mutations in MECP2 can actually have a different effect, which depends on the type of brain cell that is expressing the mutated MECP2 gene. The research, which was published in Scientific Reports, could change the way Rett syndrome, and potential therapeutic approaches are seen.
In this work, the investigators focused on how MECP2 mutations impacted mitochondria, the powerhouse organelles of the cell, in neurons and another type of brain cell called astrocytes. Previous studies have linked mitochondrial dysfunction and Rett syndrome; this research team has also revealed that mitochondria in astrocytes are particularly impaired.
The scientists cultured astrocytes that had been derived from stem cells, along with cerebral organoids, which are three-dimensional, miniaturized, and simplified versions of human brains. They were trying to get a more accurate look at what happens in Rett syndrome in human brains, instead of animal brains.
These experiments showed that astrocytes that carry Rett mutations also have misshapen mitochondria. Instead of being healthy, long ovals, the mitochondria were stubby circles. Further work revealed that these circular mitochondria were under stress, and were not pumping out as much power as they should have been.
That lack of power was causing downstream effects in astrocytes; the mitochondria were deficient in some crucial proteins, causing them to underperform. The mitochondria were not generating enough energy to power the cells, so they were breaking down proteins into amino acids instead to try to compensate for their lack of proteins. Toxic byproducts of mitochondrial metabolism, or reactive oxygen species, were also building up in the astrocytes. These aberrant mitochondria seem to cause the astrocytes to increase the activity of mitochondrial genes.
These findings contrasted sharply with what was seen in neurons; that serious dysfunction was not seen in neuronal mitochondria. But neurons rely on astrocytes for support, and sometimes even take up mitochondria from astrocytes.
This research also demonstrated that neurons take up more dysfunctional mitochondria from Rett-affected astrocytes affected than they do from unaffected astrocytes. So while neuronal mitochondria may not be affected directly, the neurons are still impacted by dysfunctional mitochondria that cause problems. Neurons with these aberrant mitochondria were shown to be hyperexcitable and toxic. Even when neurons did not carry an MECP2 mutation, these effects were seen when they were cultured with Rett astrocytes.
"This shows that in order to understand Rett syndrome, we need to look beyond what's happening in neurons to other cell types," said first study author Danielle Tomasello, PhD, a postdoctoral researcher in the lab of Whitehead Institute Founding Member Rudolf Jaenisch.
These new insights could open up novel treatment avenues.
Sources: Whitehead Institute for Biomedical Research, Scientific Reports