New research from the UNC School of Medicine has revealed unexpected roles for alpha-2-delta (α2δ) proteins in neural communication, potentially paving the way for new drug targets for various neurological disorders. Led by Samuel Young, Jr., PhD, this study challenges existing paradigms about these proteins’ functions.
Young explained that α2δ proteins are crucial in coordinating signal transmission between neurons. Genetic variations in these proteins can affect brain messaging and lead to conditions such as chronic pain, autism spectrum disorders, epilepsy, and migraines. The findings were published in Neuron.
“Our main findings basically ran counter to all the paradigms in the field,” said Young. “Through the creation of a first-of-its-kind knockout mouse model, we know much more about these complex proteins.”
The study involved creating a conditional knockout mammalian model to explore the roles of three types of α2δ proteins: α2δ1, α2δ2, and α2δ3. This model allowed researchers to investigate their functions over time and within specific neurons.
First author William Milanick led efforts to elucidate these proteins’ roles at synapses—points where information is transferred between neurons. Despite their importance as targets for anticonvulsant drugs like gabapentin and pregabalin, their precise roles remain largely unresolved.
Using the model, researchers found that synaptic functions continued even without these proteins. “We wanted to know what these α2δ proteins were necessary for,” said Young. The study confirmed that they are not essential components of synapse development or neurotransmitter release organization.
However, researchers discovered that loss of these proteins reduced levels of Munc13—a protein critical for neurotransmitter release and synaptic strength regulation. Mutations in Munc13 have been linked to frontal temporal lobe dementia and amyotrophic lateral sclerosis (ALS).
Young emphasized the need for further research into individual roles of α2δ1, α2δ2, and α2δ3 and their implications in neurological disorders.
This work received support from several institutions including the National Institutes of Health and start-up funds from the University of North Carolina-Chapel Hill.
