According to a study published in Nature today, brain astrocyte cells can be converted into neurons in live mice by turning off just one factor in the brain’s astrocyte cells. Researchers have been able to reverse neuron loss and motor deficits because of neurodegenerative illnesses, for example, Parkinson’s disease, to some extent by flipping the cellular identity switch.
“I think this is very exciting work,” says Pennsylvania State University’s Gong Chen of the Nature paper. It reaffirms that “using the brain’s internal glial cells to regenerate new neurons is a really new avenue for the treatment of brain disorders,” he continues. Chen, who is also based at Jinan University and is the chief scientific officer for NeuExcell—a company developing astrocyte-to-neuron conversion therapies—has performed such conversions in the living mouse brain by a different method but was not involved in the new study.
Dopaminergic neurons found within the substantia nigra of the brain gradually die in Parkinson’s disease. The substantia nigra is a region in the midbrain responsible for motor control. A deterioration of the dopaminergic neurons causes tremors and dyskinesia. In addition, it sometimes also affects mood and cognition, especially during the later stages of the disease.
While the symptoms can be relived using drugs, such as, levadopa, none of the drugs have the ability to stop deterioration of the patient’s neurological functions.
Researchers are investigating ways to replace missing neurons
Researchers are continuously in search of disease modifying therapies, to find ways to regenerate or replace missing neurons. An approach that is already in clinical trial includes injection of stem cell-derived neurons into the brain. The approach of using donor cells, however, is far from ideal. It runs a risk of potential immune rejection, moreover, using the patient’s own stem cells would be time-consuming and costly.
Another approach to gain momentum is to directly transform non-neuronal cells into the neurons of the midbrain. The principle is relatively simpler than injecting lab grown neurons. It has been seen that boosting the production of two transcription factors that induce neurogenesis in the brains of mice can convert astrocytes into GABAergic. Whereas, others have shown that in mouse brains, three neurogenic transcription factors can convert astrocytes into dopaminergic neurons.
The new approach relies on removing an inhibitor of neurogenesis.
The study by Xiang-Dong Fu and colleagues of University of California, San Diego shows that RNA binding protein PTB prevents the activation of neuronal factors in non-neuronal cells that can delete it and convert fibroblasts into neurons in the culture. “You . . . turn the machine on and then you don’t need it anymore,” says Fu.
It was observed that the cells began producing neuronal markers several weeks after PTB depletion. Astrocyte specific production of PTB could be switched off at will in genetically engineered mice by silencing RNA. The cells began producing neuronal markers and the number of ex-astrocytes producing such markers increased as the weeks went by. Injections at different sites of the brain induced different types of neurons. The highest abundance of dopaminergic neurons was produced at the substantia nigra, suggesting that the PTB inhibition enables neuron conversion.
The team then tested its method in mice whose substantiae nigrae were injected with 6-hydroxydopamine—a dopamine analog toxic to dopaminergic neurons—to mimic Parksinon’s disease. They showed that astrocyte-specific PTB depletion in these mice boosted the numbers of dopamine neurons and the production of dopamine itself, and improved the animals’ motor functions within three months of the treatment. Animals that did not receive PTB-depletion treatment showed poorer limb use and increased rotational movements—both standard measures of motor function impairments caused by dopaminergic neuron loss—compared with treated animals. The recent paper in Cell by an independent group has shown similar results.
“The results . . . present intriguing possibilities for cell replacement strategies,” says Marina Emborg, a Parkinson’s disease researcher at the University of Wisconsin-Madison.
She further stated:
“The safe clinical translation of this method will need to consider whether the number of astrocytes present in the [patient] brain is enough for effective cell replacement and whether shifting astrocytes into neurons affects brain homeostasis.” Also, the researchers will “need to assess whether the changed cells remain with a neuronal phenotype and for how long they survive.”
However, according to Fu, the approach does not work as effectively in older animals compared to younger ones. While the experiments in young mice work very well, the disease affects the elderly. Therefore, it “is a critical thing” to show that the cells can be converted at older ages.
References
H. Qian et al., “Reversing a model of Parkinson’s disease with in situ converted nigral neurons,” Nature, doi:10.1038/s41586-020-2388-4, 2020.
H. Zhou et al., “Glia-to-neuron conversion by CRISPR-CasRx alleviates symptoms of neurological disease in mice,” Cell, doi:10.1016/j.cell.2020.03.024, 2020.
