Reversing a model of Parkinson’s disease with in situ converted nigral neurons
Summary by Giuseppe Madaro
Background
The DNA in our cells works like a library containing all the information required to build a human being. The books in this library are called “genes” and each of them contains the instructions for making a specific cell component. Not all the cell components are needed at the same time and in the same amount, so cells need to regulate how often specific genes are used. This occurs by means of a wide range of mechanisms known as “gene expression regulation”, carried out by specialised “librarians”, the gene expression regulators. These “librarians” control each other’s work and have different reading preferences based on the cell type. Consequently, different cells use a different combination of genes, which results in cells achieving different structures and functions to meet their challenge. For example, in the brain we can find cells such as neurons, which transmit electrical impulses and produce chemical messengers called neurotransmitters, and astrocytes, star-shaped cells that hold neurons in place and help them develop and work the way they should.
High cells specialisation means that they are useful in performing specific tasks within the body. However, this makes some cells irreplaceable and can sometimes lead to cell type- specific diseases. In people with Parkinson’s disease, there is a progressive loss of a type of neurons that produce the neurotransmitter dopamine. These neurons are part of neuronal circuits controlling many motor and non-motor body functions, like walking and thinking. Their disruption results in shaking, limbs stiffness and problems with balance. People with Parkinson’s disease often experience changes in the way they learn, remember, think, process their emotions and behave.
Why is the study important?
We still don’t know what causes Parkinson’s disease and we currently cannot rely on any treatments to prevent further loss of nerve cells, known as neurodegeneration.
What did the authors do and how did they do it?
Qian and colleagues have proposed to contrast neurodegeneration by directly converting astrocytes into dopamine-producing neurons in the areas of the brain affected by Parkinson’s disease. This is possible by eliminating a gene expression regulator called PTB by targeting astrocytes with a drug that specifically interferes with the production of PTB. In these conditions, the remaining gene expression regulators take over the DNA “library” causing a change in the set of genes that these cells express and turning them into neurons.
What are the results?
These “reprogrammed” neurons appear and behave like normal neurons; some of them produce dopamine and fit into the neuronal circuits disrupted by Parkinson’s disease. This one-step conversion approach has been successfully used to restore the normal motor functions in mice mimicking some features of the disease.
What do the finding mean going forward for people with the disease?
The study shows an innovative approach for replacing- at least in part- the nerve cells lost because of a brain disease. However, this is just a rudimentary tool in the hands of scientists that requires some refinement. In fact, mice are relatively simple animals and we still do not know if this is safe and effective on humas. More research in human models will help clarify this.
This study can be found at: https://doi.org/10.1038/s41586-020-2388-4
Paper title: Reversing a model of Parkinson’s disease with in situ converted nigral neurons
Author list: 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
Publication details: Nature volume 582, pages 550–556 (2020); Published on the 24th of June 2020