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

Date:
June 25, 2020
Source:
University of California - San Diego
Summary:
Researchers have discovered that a single treatment to inhibit a
gene called PTB in mice converts native astrocytes, brain support
cells, into neurons that produce the neurotransmitter dopamine. As
a result, the mice's Parkinson's disease symptoms disappear.



FULL STORY ========================================================================== [Astrocytes illustration | Credit: (c) Kateryna_Kon / stock.adobe.com] Astrocytes illustration (stock image).

Credit: (c) Kateryna_Kon / stock.adobe.com [Astrocytes illustration |
Credit: (c) Kateryna_Kon / stock.adobe.com] Astrocytes illustration
(stock image).

Credit: (c) Kateryna_Kon / stock.adobe.com Close 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.

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.



==========================================================================
The study is published June 24, 2020 in Nature.

"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 Fu, who is a Distinguished 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." There are several different ways to mimic Parkinson's disease in mice. In this case, the researchers applied a
dopamine look-a-like molecule to poison neurons that produce dopamine. As
a result, the mice lose dopamine-producing neurons and develop symptoms
similar to Parkinson's disease, such as movement deficiencies.

The treatment works like this: The researchers developed a noninfectious
virus that carries an antisense oligonucleotide sequence -- an artificial
piece of DNA 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, also known as designer DNA drugs, are a
proven approach for neurodegenerative and neuromuscular diseases --
study co-author, Don Cleveland, PhD, pioneered the technology, and it
now forms the basis for a Food and Drug Administration (FDA)-approved
therapy for spinal muscular atrophy and several other therapies currently
in clinical trials. Cleveland is chair of the Department of Cellular and Molecular Medicine at UC San Diego School of Medicine and member of the
Ludwig Institute for Cancer Research, San Diego.



==========================================================================
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 percent. 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
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, Distinguished 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? "I intend to spend the rest of my career answering
these questions."

========================================================================== Story Source: Materials provided by
University_of_California_-_San_Diego. Original written by Heather
Buschman, PhD. Note: Content may be edited for style and length.


========================================================================== Journal Reference:
1. Hao Qian, Xinjiang Kang, Jing Hu, Dongyang Zhang, Zhengyu Liang, Fan
Meng, Xuan Zhang, Yuanchao Xue, Roy Maimon, Steven F. Dowdy, Neal K.

Devaraj, Zhuan Zhou, William C. Mobley, Don W. Cleveland,
Xiang-Dong Fu.

Reversing a model of Parkinson's disease with in situ
converted nigral neurons. Nature, 2020; 582 (7813): 550 DOI:
10.1038/s41586-020-2388-4 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2020/06/200625102540.htm

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