Biology

PTB Inhibition Converts Astrocytes into Neurons, Reverses Symptoms in a Mouse Model of Parkinson's Disease


Researchers here expand upon a fortuitous discovery that inhibition of the gene PTB causes a number of cell types to change into neurons, using this finding as the basis for a treatment that might be applied to a range of neurodegenerative conditions in which neurons are lost. When used in an animal model of Parkinson’s disease, PTB inhibition causes astrocytes, a class of supporting cell in the brain, to become neurons. Symptoms of the condition are removed, indicating that some of the former astrocytes take over the duties of the vital population of dopaminergenic neurons that is lost in Parkinson’s disease.

Several years ago, a postdoctoral researcher was using a technique called siRNA to silence the PTB gene in connective tissue cells known as fibroblasts. It’s a tedious process that needs to be performed over and over. He got tired of it and instead used 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 PTB transforms several types of mouse cells directly into neurons.

Recently, researchers applied this finding 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, Parkinson’s disease symptoms disappeared. 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.

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.

Link: https://ucsdnews.ucsd.edu/pressrelease/one-time-treatment-generates-new-neurons-eliminates-parkinsons-disease-in-mice

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