Don W. Cleveland: One-time treatment generates new neurons, eliminates Parkinson’s disease in mice

June 25, 2020

In a major breakthrough, NOMIS Awardee Don W. Cleveland and colleagues have identified a potentially powerful and chemically feasible approach to treating Parkinson’s disease by replacing lost neurons. Their findings were published in Nature.

One-time treatment generates new neurons, eliminates Parkinson’s disease in mice

Inhibiting a single gene converts many cell types directly into dopamine-producing neurons

June 24, 2020 | Heather Buschman, PhD

Xiang-Dong Fu, PhD, has never been more excited about something in his entire career. He has long studied the basic biology of RNA, a genetic cousin of DNA, and the proteins that bind it. But a single discovery has launched Fu into a completely new field: neuroscience.

For decades, Fu and his team at University of California San Diego School of Medicine studied a protein called PTB, which is well known for binding RNA and influencing which genes are turned “on” or “off” in a cell. To study the role of a protein like PTB, scientists often manipulate cells to reduce the amount of that protein, and then watch to see what happens.

Left: mouse astrocytes (green) before reprogramming; Right: neurons (red) induced from mouse astrocytes after reprogramming with PTB antisense oligonucleotide treatment. (Photo: UC San Diego)

Several years ago, a postdoctoral researcher working in Fu’s lab was taking that approach, using a technique called siRNA to silence the PTB gene in connective tissue cells known as fibroblasts. But it’s a tedious process that needs to be performed over and over. He got tired of it and convinced Fu they should use a different technique to create a stable cell line that’s permanently lacking PTB. At first, the postdoc complained about that too, because it made the cells grow so slowly.

But then he noticed something odd after a couple of weeks — there were very few fibroblasts left. Almost the whole dish was instead filled with neurons.

In this serendipitous way, the team discovered that inhibiting or deleting just a single gene, the gene that encodes PTB, transforms several types of mouse cells directly into neurons.

More recently, Fu and Hao Qian, PhD, another postdoctoral researcher in his lab, took the finding a big step forward, applying it in what could one day be a new therapeutic approach for Parkinson’s disease and other neurodegenerative diseases. Just a single treatment to inhibit PTB in mice converted native astrocytes, star-shaped support cells of the brain, into neurons that produce the neurotransmitter dopamine. As a result, the mice’s Parkinson’s disease symptoms disappeared.