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.”

Mouse brain before reprogramming, with dopaminergic neurons shown in green. Bottom: Mouse brain after reprogramming with PTB antisense oligonucleotide treatment, which converted astrocytes into more dopaminergic neurons (green). [UC San Diego Health Sciences]
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 striatum is accompanied by restoration of dopamine levels and rescue of motor deficits.”

Antisense oligonucleotide treatment

The treatment works like this: The researchers developed a noninfectious virus that carries an antisense oligonucleotide sequence designed to specifically bind the RNA coding for PTB, thus degrading it, preventing it from being translated into a functional protein and stimulating neuron development.

Antisense oligonucleotides are a proven approach for neurodegenerative and neuromuscular diseases which forms the basis for an FDA-approved therapy for spinal muscular atrophy and several other therapies currently in clinical trials.

The researchers administered the PTB antisense oligonucleotide treatment directly to the mouse’s midbrain, which is responsible for regulating motor control and reward behaviors, and the part of the brain that typically loses dopamine-producing neurons in Parkinson’s disease. A control group of mice received mock treatment with an empty virus or an irrelevant antisense sequence.

In the treated mice, a small subset of astrocytes converted to neurons, increasing the number of neurons by approximately 30%. Dopamine levels were restored to a level comparable to that in normal mice. What’s more, the neurons grew and sent their processes into other parts of the brain. There was no change in the control mice.

By two different measures of limb movement and response, the treated mice returned to normal within three months after a single treatment and remained completely free from symptoms of Parkinson’s disease for the rest of their lives. In contrast, the control mice showed no improvement.

“I was stunned at what I saw,” said study co-author William Mobley, MD, PhD, professor of neurosciences at UC San Diego School of Medicine. “This whole new strategy for treating neurodegeneration gives hope that it may be possible to help even those with advanced disease.”

What is it about PTB that makes this work? “This protein is present in a lot of cells,” Fu said. “But as neurons begin to develop from their precursors, it naturally disappears. What we’ve found is that forcing PTB to go away is the only signal a cell needs to turn on the genes needed to produce a neuron.”

Of course, mice aren’t people, he cautioned. The model the team used doesn’t perfectly recapitulate all essential features of Parkinson’s disease. But the study provides a proof of concept, Fu said.

Next, the team plans to optimize their methods and test the approach in mouse models that mimic Parkinson’s disease through genetic changes. They have also patented the PTB antisense oligonucleotide treatment in order to move forward toward testing in humans.

“It’s my dream to see this through to clinical trials, to test this approach as a treatment for Parkinson’s disease, but also many other diseases where neurons are lost, such as Alzheimer’s and Huntington’s diseases and stroke,” Fu said. “And dreaming even bigger—what if we could target PTB to correct defects in other parts of the brain, to treat things like inherited brain defects?” Fu asserted that he intends “to spend the rest of my career answering these questions.”

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