Discovery Stabilizes Sodium Channel, May Avert Seizures
Controlling a biological reaction that stabilizes part of the sodium channel in nerve cells can become a new approach to prevent epileptic seizures, according to a mouse study.
This reaction, called neddylation, stabilizes the NaV1.1. subunit of the sodium channel, in which mutations are responsible for the development of Dravet syndrome.
“Our finding that neddylation can prevent epilepsy in mouse models represents a new direction for future research,” Lin Mei, MD, PhD, professor and chair of the Department of Neurosciences at Case Western Reserve School of Medicine, said in a press release. “With this new lead, scientists or pharmaceutical companies can look for chemicals to boost neddylation.”
Epilepsy is a central nervous system condition characterized by seizures or periods of unusual behavior, and sometimes loss of awareness.
Maintaining an appropriate balance of electrical activity in the brain is essential for adequate communication between nerve cells. The basis of this communication is achieved through adequate stimulation of nerve cells, namely throughout excitatory and inhibitory neurons.
Excitatory signaling from one nerve cell to the next makes the latter cell more likely to fire an electrical signal. Inhibitory signaling makes the latter cell less likely to fire. If inhibitory neurons fail to suppress excitatory neurons, these can become overactive and cause seizures.
“This balance between excitatory and inhibitory neurons is absolutely important for everything that we do,’’ Mei said. “When the balance is tilted, so that excitatory neurons are super active, there will be a problem. It’s highly likely there will be epilepsy.’’
Proper function of sodium voltage-gated channels is necessary for the excitability of inhibitory neurons. They conduct currents of sodium ions down their electrochemical gradient into the cell.
In Dravet syndrome, about 80–90% of patients carry mutations in SCN1A, a gene that encodes for one part of the sodium channel called NaV1.1. This leads to the misfiring of excitatory neurons and, consequently, seizures. However, very little is known about the mechanisms that regulate NaV1.1 stability or expression.
Researchers hypothesized that neddylation, a known reaction that biologically changes proteins, could be involved in the function of inhibitory neurons.
To test this theory, the team engineered mice that lacked a protein needed for neddylation — NAE1 — in inhibitory neurons. As a result, these mice had epileptic seizures, uncoordinated walking and other neurological symptoms.
Electrophysiological studies revealed that neddylation was critical to control the excitability of inhibitory neurons. Importantly, the NaV1.1 subunit of the sodium channel became unstable in the absence of neddylation, resulting in decreased levels of this protein and in a reduction in sodium-current density.
When researchers genetically manipulated the mutant mice to start producing more NaV1.1, they were able to restore inhibitory neuron excitability.
“Our findings describe a role of neddylation in maintaining NaV1.1 stability for [inhibitory neuron] excitability and reveal what we believe is a new mechanism in the pathogenesis of epilepsy,” the researchers wrote.
According to Mei, the next phase in their research is to develop treatments or discover strategies that can manipulate neddylation and stabilize NaV1.1. “The concept is still in an early stage and much needs to be done to make a difference for patients,” he said.
The team is currently carrying out more experiments to determine if this applies to patients with other types of epilepsy.