Using human nerve cells and three-dimensional “mini brains,” researchers have found that dysfunctional potassium channels may underlay the development of seizures associated with Angelman syndrome.
Their study, “Potassium channel dysfunction in human neuronal models of Angelman syndrome,” was published in the journal Science.
Angelman syndrome (AS) is a complex genetic disorder that primarily affects the nervous system, and is characterized by developmental delay, learning disabilities, speech difficulties, and physical incapacity. Seizures are also a common symptom, affecting around 90% of patients.
The disease is caused by genetic defects in the UBE3A gene, which compromises the production of an enzyme called ubiquitin protein ligase E3A in certain areas of the brain. This enzyme flags other proteins to be degraded, as part of the natural cellular process for removing damaged or unnecessary proteins.
UBE3A plays a critical role in the development and function of the nervous system, helping to balance protein levels at the synapse — the junction between two nerve cells that allows them to communicate.
The team found that specific ion channels, called large conductance calcium- and voltage-activated big potassium (BK) channels — which allow potassium to pass through cells — were dysregulated in AS neurons. This seemed to be one of the reasons why AS patients frequently experience seizures.
In normal neurons, the UBE3A enzyme targets these ion channels for degradation, but in neurons from AS patients, the absence of a functional enzyme leads to the accumulation of an excessive number of potassium channels.
Too many of these channels leads to the hyperactivity of brain networks which, in turn, results in epileptic seizures.
When researchers treated neurons with agents that specifically block these potassium channels, normal brain network activity was restored in both human and mouse neurons. Importantly, upon treatment, seizure severity was reduced in an AS mouse model.