Transforming mature neurons into dopamine factories could help fight brain diseases

Scientists in regenerative medicine have long believed that turning one type of mature cell into another is impossible without first reverting the original cell back into a stem cell. But now a team of researchers at the University of Texas Southwestern Medical Center has successfully turned mature inhibitory neurons into dopamine-producing neurons—and they did it by accident.

The team, led by Chun-Li Zhang, Ph.D., a professor of molecular biology at the center, originally set out to make dopamine-producing neurons out of glial cells in live mouse brains. But according to results published in the journal Stem Cell Reports, they instead turned the mature neurons into dopaminergic neuron-like cells. They believe their inadvertent discovery could be used to treat neurological diseases.

Dopaminergic neurons in the brain produce dopamine, which is important for controlling voluntary movement and the motivation-reward system that drives behavior. The loss of dopamine-producing cells is linked to neurological disorders like Parkinson’s disease, and scientists are on the hunt for new methods of replenishing these vital neurons.

Glial cells, which surround neurons and provide protective support, can regenerate and multiply easily, thus making them better candidates as potential neuron replacement therapies. That’s why Zhang and his team targeted them in the first place.

They injected a mixture of cell reprogramming promoters into the mouse’s striatum. These include valproic acid, a stem cell factor called SOX2—which previous studies showed can change glial cells into neural progenitors—and three dopaminergic neuron-specific transcription factors that regulate gene expression.

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To the team’s dismay, the glia remained unchanged; instead, so-called GABAergic medium spiny neurons that are plentiful within the striatum—and key in controlling movements—had transformed into cells that behaved like dopaminergic neurons. These new cells displayed rhythmic activity and formed network connections, much like dopaminergic cells do, although they retained some of their original features.

Most importantly, the team found that the new cells came into being without passing through a stem cell-like transition phase.

“To our knowledge, changing the phenotype of resident, already-mature neurons has never been accomplished before,” said Zhang in a statement. “This could mean that no cell type is fixed even for a functional, mature neuron.”

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Other methods are being explored to reduce or reverse dopaminergic neurodegeneration. South Korea biotech Peptron, for example, is repurposing a GLP-1 receptor agonist, a common class of Type 2 diabetes therapy, after a study showed promise in mouse models of Parkinson's. Appello Pharmaceuticals is pushing ahead with a technology licensed from Vanderbilt University. Instead of replacing dopamine, this startup explores the use of what’s called mGlu4 modulators to control the neurotransmitters glutamate and GABA, which are produced by the same neurons that Zhang’s team had accidentally reprogrammed.

Zhang believes UT Southwestern's new discovery should be further investigated in the treatment of Parkinson's and related disorders. “Such knowledge may one day be applied to devise therapeutic strategies for treating neurological diseases through reprogramming the phenotype of local neurons,” the team wrote in the study.