Oxidative stress could potentially be a significant factor in the development of AS symptoms, according to initial research
In a groundbreaking study published in Molecular Psychiatry, scientists in Israel have uncovered significant insights into the role of oxidative stress and mitochondrial dysfunction in early brain development in individuals with Angelman syndrome (AS).
AS, a neurodevelopmental disorder characterised by intellectual disability, behavioural challenges, and seizures, is caused by the loss or malfunction of the maternally inherited UBE3A gene. The UBE3A enzyme is critical in certain areas of the brain, and its loss leads to severe neurological symptoms.
The team, led by Dr. Shai Shaham, examined mitochondrial function and reactive oxygen species (ROS) levels during early AS brain development using neural precursor cells (NPCs) from healthy and genetically engineered AS mouse embryos.
The findings indicate that oxidative stress and mitochondrial dysfunction may play a key role in driving AS symptoms via an altered susceptibility to apoptosis, or programmed cell death. NPCs from AS mice exhibited enhanced apoptosis and changes in mitochondrial function consistent with vulnerability to cell death and enhanced mitochondrial ROS production.
Interestingly, AS cells had low levels of glutathione, a molecule that helps defend mitochondria against oxidative environments. The reduction of glutathione in the cell cultures led to significant increases in cell death, supporting the idea that alteration of glutathione levels in AS NPCs play a role in their vulnerability to apoptosis.
Treatment with glutathione, which naturally fights oxidative stress, was able to reverse some of the abnormalities observed in the study. When the cells were supplemented with glutathione, ROS levels were reduced, as was the rate of apoptosis, but some mitochondrial alterations remained.
While ROS signaling does play a necessary role during neural development, the developing brain is "highly susceptible to oxidative stress," as Dr. Shaham explains. Some recent studies have suggested that a UBE3A deficiency affects the function of mitochondria, the energy production centers of cells, thereby driving oxidative stress in certain parts of the brain.
The knowledge gained from these studies may pave the way toward novel therapeutic approaches addressing mitochondrial-related anomalies in early brain development, not only for AS but also other neurodevelopmental disorders. The team noted that further studies are warranted to better understand the relationship between UBE3A and oxidative stress in early AS development.
Symptoms of AS can be observed in children as young as 6 months old, but most are diagnosed between 9 months and 6 years old. As our understanding of the underlying mechanisms of this disorder deepens, so too does the hope for more effective treatments and, ultimately, a cure.
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