Like many other neurodegenerative diseases, there are no disease-modifying treatments available for Parkinson’s disease. Characterized by the loss of dopaminergic neurons in the substantia nigra region of the brain, most treatment strategies aim to prevent neuronal loss or protect vulnerable neuronal circuits. Another strategy is to replace the lost neurons by creating new neurons that produce dopamine. And, a team from the University of California (UC), San Diego School of Medicine, has just achieved that goal, in mice.
In the paper, “Reversing a model of Parkinson’s disease with in situ converted nigral neurons,” published in Nature, the team reported an “efficient one-step conversion of isolated mouse and human astrocytes to functional neurons.” They achieved this by depleting the RNA-binding protein PTB.
“Researchers around the world have tried many ways to generate neurons in the lab, using stem cells and other means, so we can study them better, as well as to use them to replace lost neurons in neurodegenerative diseases,” said Xiang-Dong Fu, PhD, professor in the department of cellular and molecular medicine at UC San Diego School of Medicine. “The fact that we could produce so many neurons in such a relatively easy way came as a big surprise.”
Fu and his team study the PTB protein (also known as PTBP1), a well-known RNA binding protein that influences gene expression in a cell. Several years ago, the Fu lab used siRNA to silence the PTB gene in fibroblasts. They also created a stable cell line that’s permanently lacking PTB which led to the discovery that mouse cells lacking PTB are transformed into neurons.
Applying this approach to the mouse brain, they demonstrated “progressive conversion of astrocytes to new neurons that innervate into and repopulate endogenous neural circuits.” The authors added that astrocytes from different brain regions are converted to different neuronal subtypes.
In mice, just a single treatment to inhibit PTB in mice converted native astrocytes into neurons that produce the neurotransmitter dopamine. As a result, the mice’s Parkinson’s disease symptoms disappeared.
The team used a chemically induced model of Parkinson’s disease in mice, in which the mice lose dopamine-producing neurons and develop symptoms similar to Parkinson’s disease, such as movement deficiencies.
Using these mice, the researchers showed conversion of midbrain astrocytes to dopaminergic neurons, which provide axons to reconstruct the nigrostriatal circuit. Notably, “re-innervation of the striatum is accompanied by restoration of dopamine levels and rescue of motor deficits.”