Oxidative stress may play key role in driving AS symptoms: Early study
Treatment with glutathione was able to reverse some abnormalities in nerve cells
Oxidative stress and mitochondrial dysfunction during early brain development may contribute to symptoms in people with Angelman syndrome (AS), according to a recent study.
These cellular changes were observed in developing nerve cells taken from mouse embryos with AS-like disease, but not their healthy counterparts, and were associated with higher than normal cell death.
Treatment with glutathione, which naturally fights oxidative stress, was able to reverse some of these abnormalities.
The study, “Elevated ROS levels during the early development of Angelman syndrome alter the apoptotic capacity of the developing neural precursor cells,” was published in Molecular Psychiatry.
Angelman syndrome is caused by the loss or malfunction of the maternally inherited UBE3AÂ gene, which provides instructions for making an enzyme of the same name.
Since the UBE3A enzyme inherited from one’s mother is critical in certain areas of the brain, patients experience severe neurological symptoms including behavioral changes, and intellectual and physical disabilities.
Children with Angelman can show symptoms as young as 6 months old, but most are diagnosed between 9 months and 6 years old.
The cellular consequences of the loss of UBE3A are very complex and not completely understood.
Some recent studies have suggested that a UBE3A deficiency affects the function of mitochondria, the so-called energy production centers of cells, thereby driving oxidative stress in certain parts of the brain.
What is oxidative stress?
Oxidative stress is a type of cellular damage that results from an imbalance between toxic reactive oxygen species (ROS) produced in the mitochondria and the antioxidant defense systems that combat them.
While ROS signaling does play a necessary role during neural development, the developing brain is “highly susceptible to oxidative stress,” the researchers wrote. Thus, too much ROS could contribute to excessive cell death during embryonic development that drives later brain dysfunction.
In the study, scientists in Israel more closely examined mitochondrial function and ROS levels during early AS brain development.
To do so, they obtained neural precursor cells (NPCs) from mouse embryos that were healthy or genetically engineered to have AS.
In cell cultures, NPCs from AS mice exhibited enhanced apoptosis, a type of programmed cell death, relative to their healthy counterparts.
Moreover, changes in mitochondrial function that would be consistent with vulnerability to cell death and enhanced mitochondrial ROS production were observed.
Notably, AS cells had low levels of glutathione, a molecule that helps defend mitochondria against oxidative environments that drive their dysfunction.
When the cells were supplemented with glutathione, ROS levels were reduced, as was the rate of apoptosis, but some mitochondrial alterations remained.
Findings may apply to other neurodevelopmental disorders
To further validate the potential importance of glutathione in AS, the researchers treated the cell cultures with a compound to deplete it.
That reduction led to significant increases in cell death, overall supporting the “notion that alteration of glutathione levels in AS NPCs play a role in their vulnerability to apoptosis.”
While some apoptosis is necessary for early brain development, too much can lead to structural and functional deficits that permanently impair brain function.
Altogether the findings indicate that oxidative stress and mitochondrial dysfunction may play a key role in driving AS symptoms via an altered susceptibility to apoptosis, according to the researchers.
The team noted that further studies are warranted to better understand the relationship between UBE3A and oxidative stress in early AS development.
“This knowledge will pave the way toward novel therapeutic approaches addressing mitochondrial-related anomalies in early brain development, not only of AS pathogenesis but also other neurodevelopmental disorders,” the team concluded.
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