Dopamine neuron regeneration brings new hope for Parkinson's disease treatment

In our brain, in addition to neurons that transmit and process information, there are also glial cells that far outnumber neurons - such as astrocytes, which can provide protection and support for neurons.

In a study published this week in Nature, a research team from the University of California, San Diego successfully converted astrocytes in the mouse brain into functional dopamine neurons, bringing new possibilities for treating Parkinson's disease.

The research is featured on the cover of this issue of Nature | Lantao Gou

Parkinson's disease, like Alzheimer's disease, is a common neurodegenerative disease for which there is currently no effective treatment. Parkinson's disease is more common in the elderly, but more and more young people are also suffering from it. Boxing King Muhammad Ali was diagnosed with Parkinson's disease at the age of 42.

The typical symptoms of Parkinson's disease are tremors and slow movements of the hands when at rest, and the patient's cognitive function is also affected. From a pathological point of view, an important feature of Parkinson's disease is the death of a large number of dopamine neurons in the substantia nigra region of the midbrain (part of the brainstem), which may be related to the patient's abnormal motor function.

Parkinson's disease as described in the 1886 Manual of Diseases of the Nervous System | William Richard Gowers

Astrocytes produce a protein called PTBP1, which can hinder the transformation of cells into neurons. The researchers isolated astrocytes from mouse and human brains and reduced the expression of the Ptbp1 gene in the cells. After 4 weeks, 50-80% of the astrocytes transformed into neurons; among them, the neurons transformed by astrocytes in the midbrain expressed genes specifically expressed by dopamine neurons - that is, they were similar to dopamine neurons in the brain.

Schematic diagram of the transformation of astrocytes into neurons (PTB is PTBP1 protein) | Nature

Subsequently, the researchers injected mice with a virus that could reduce the expression of the Ptbp1 gene. After 12 weeks, more than 30% of the virus-infected astrocytes were converted into dopamine neurons with normal physiological functions. The projection from the substantia nigra to the striatum plays an important role in motor control. Compared with healthy mice, the dopamine content in the striatum of Parkinson's mice was only 25%; after this treatment, dopamine increased to 65%.

In addition, the researchers also tried to directly inject antisense oligonucleotides (a type of chemically modified short-chain nucleic acid) that interfere with Ptbp1 into the midbrain, which also achieved good therapeutic effects; and compared with viruses, this method is more clinically feasible.

Using antisense oligonucleotides, mouse astrocytes (green) were induced to become neurons (red) | UC San Diego Health Sciences

Dopamine neurons (green) increased in mice after antisense oligonucleotide treatment | UC San Diego Health Sciences

In addition to Parkinson's disease, this work is also expected to be applied to other neurodegenerative diseases. However, it still has a long way to go before it can be used in clinical treatment.

References

Qian, H., Kang, X., Hu, J. et al. Reversing a model of Parkinson's disease with in situ converted nigral neurons. Nature 582, 550–556 (2020). https://doi.org/10.1038/s41586-020-2388-4

Author: Insulindian

Editor: Mai Mai

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