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SAN DIEGO – Sometimes, scientific breakthroughs occur when researchers aren’t exactly looking for them. While attempting to better understand the function of a protein in connective tissue cells, UC San Diego School of Medicine scientists found a way to transform multiple types of cells into neurons. This discovery has led to the development of a treatment that eliminates symptoms of Parkinson’s disease in mice.
The protein researchers were studying, called PTB, is known for its general role in activating or deactivating genes within a cell. In an attempt to better understand how PTB contributes to cell function, researchers silenced the PTB gene using a technique called siRNA in a type of connective tissue cell, known as a fibroblast. The researchers grew the fibroblasts in petri dishes, silenced PTB, and waited a couple of weeks to check on the fibroblasts and observe any changes.
Left: mouse astrocytes (green) before reprogramming; Right: neurons (red) induced from mouse astrocytes after reprogramming with PTB antisense oligonucleotide treatment. (Image credit: UC San Diego Health Sciences) When the researchers checked the fibroblasts, they were shocked. They found that very few fibroblasts remained in the dishes. Instead, the dishes contained mostly neurons. Unintentionally, they had discovered a way to turn fibroblasts into neurons.
In subsequent experiments, the researchers found that they could also turn other cells into neurons. When they silenced PTB in a type of non-neuronal brain cell known as an astrocyte, they were also able to generate neurons.
“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,” says lead author of the study, Xiang-Dong Fu, in a release. “The fact that we could produce so many neurons in such a relatively easy way came as a big surprise.”
Fu is a Distinguished Professor in the Department of Cellular and Molecular Medicine at UC San Diego School of Medicine.
Scientists ‘stunned’ after Parkinson’s disease test
Once researchers realized that they could easily create neurons from other types of cells, they decided to see if the method could be used to treat neurodegenerative diseases, such as Parkinson’s disease. In Parkinson’s, dopamine cells in the brain die. Thus, to assess their method, the researchers used a chemical that poisons dopamine neurons and creates symptoms of Parkinson’s disease in mice.
After using the chemical to kill dopamine neurons in the mice, researchers silenced PTB. They found that 30% of astrocytes turned into neurons. Moreover, these newly generated neurons seemed to grow normally and even began to send connections to other parts of the brain, like normal neurons.
When the researchers looked at mouse behavior, they also found that silencing PTB completely restored movement function. Moreover, even though the PTB-silencing treatment was only administered once, the mice did not show any symptoms of Parkinson’s disease for the remainder of their lifetime.
“I was stunned at what I saw,” said study co-author Dr. William Mobley, Distinguished Professor of Neurosciences at UCSD’s School of Medicine. “This whole new strategy for treating neurodegeneration gives hope that it may be possible to help even those with advanced disease.”
Not quite ready for humans
While the treatment is promising for the treatment of neurodegenerative diseases in humans, it still needs to go through more rigorous testing before being ready for human trials. In the next steps, the researchers plan to test the method with other mouse models of Parkinson’s disease. These models involve genetic changes rather than chemical destruction of dopamine neurons.
The researchers have also patented their treatment in hopes of moving it forward to 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 says. “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?”
“I intend to spend the rest of my career answering these questions,” he says.
It would be wonderful if this works in humans, too, but given what Bret Weinstein has to say about extra-long telomeres in lab mice skewing study results, I won't hold my breath for an effective drug. Scroll forward to the last 20 minutes:
Be kinder than necessary because everyone you meet is fighting some kind of battle.
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