Study detects changes in how diseased neurons sense and use oxygen

Scientists from Carnegie Mellon University have devised a new method for isolating a kind of brain cell that is related to symptoms of Parkinson’s disease. The new method allows them to perform an in-depth study of that cell type.

Parkinsons Disease

Image Credit: Orawan Pattarawimonchai/Shutterstock.com

According to Alyssa Lawler, a Ph.D. student in biological sciences, the new method works only in exclusively bred mice and is less expensive compared to earlier methods for isolating the brain cells, said. She and her collaborators have used it to identify previously unexplored changes to how the diseased neurons sense and use oxygen.

The new method and the study results have been described in a research paper published online by the JNeurosci journal.

Even a small chunk of brain tissue can have dozens of different cell types. Each of these cell types has different roles in the behavior of an animal and also in disease.”

Andreas Pfenning, Assistant Professor, Computational Biology Department, Carnegie Mellon University

Thus, isolating cells of a specific type from their neighbors is a crucial first step for scientists who wish to explore them.

In this study, the focus of the researchers was on parvalbumin-expressing (PV+) neurons, which have been found to involve in Parkinson’s disease by the laboratory of Aryn Gittis, associate professor of biological sciences. When these cells are stimulated, mice with Parkinson’s symptoms regain motor control and their capability to run.

Laboratory mice were bred with PV+ cells that include a protein known as Cre, which stimulates a fluorescent green protein. That fluorescence enables cell-sorting machines to separate the cells from others in a mixture.

However, cell-sorting machines are very costly, and therefore, Lawler devised a cost-effective method, known as Cre-Specific Nuclear Anchored Independent Labeling, or cSNAIL.

The new method involves using a virus often employed by scientists to transfer DNA to brain cells. When the virus penetrates PV+ cells, Cre makes the tag to fluoresce. According to Lawler, the tag, fixed to the cell nucleus, can endure even when the tissues are cut off. Then, scientists employ antibodies to identify the tag and drag the PV+ nuclei apart from the others.

The technique turned out to be really specific, really efficient,” Lawler stated, noting that it can be modified according to other mouse models that utilize the Cre protein.

In a later analysis of the PV+ neurons, the team identified that those from sick mice synthesized more RNA that takes part in the expression of genes for sensing or using oxygen. An additional study also demonstrated that the DNA in the nucleus uncoiled in ways suggesting that the oxygen-sensing genes were more active.

Oxygen-sensing pathways have been implicated in other, earlier aspects of Parkinson’s disease, but not previously in PV+ cells.”

Alyssa Lawler, PhD Student in Biological Sciences, Carnegie Mellon University

These pathways play a role in both safeguarding and killing cells through neurodegeneration.

According to Pfenning, datasets from this study are associated with a larger effort to develop machine learning models that could enable scientists to understand disease mechanisms by watching how specific DNA sequences react to various conditions across different types of cells.

We’re learning how to talk to cells, to speak their language.”

Alyssa Lawler, PhD Student in Biological Sciences, Carnegie Mellon University

Source:
Journal reference:

Lawler, A. J., et al. (2020) Cell type-specific oxidative stress genomic signatures in the globus pallidus of dopamine depleted mice. Journal of Neuroscience. doi.org/10.1523/JNEUROSCI.1634-20.2020.

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