Parkinson’s disease (PD) is a progressive disorder that affects nerve cells in the brain responsible for body movement. When dopamine-producing neurons die, symptoms such as tremor, slowness, stiffness, and balance problems occur.

Researchers at Carnegie Mellon University (CMU) have developed a new method for isolating a type of brain cell associated with Parkinson’s disease symptoms, enabling them to study that cell type in detail.

Their new method and findings are published in the journal JNeurosci in a paper titled, “Cell type-specific oxidative stress genomic signatures in the globus pallidus of dopamine depleted mice.”

“…Despite the distinct roles these cell types play in the neural circuit, the molecular correlates remain unknown due to the difficulty of isolating rare neuron subtypes. To address this issue, we developed a new viral affinity purification strategy, Cre-Specific Nuclear Anchored Independent Labeling (cSNAIL), to isolate Cre recombinase-expressing (Cre+) nuclei from the adult mouse brain,” the researchers wrote.

“Even a small chunk of brain tissue can have dozens of different cell types,” explained Andreas Pfenning, an assistant professor in CMU’s computational biology department. “Each of these cell types has different roles in the behavior of an animal and also in disease.” Separating cells of a certain type from their neighbors is thus a critical first step for researchers who want to study them.

The researchers focused on parvalbumin-expressing (PV+) neurons, which have been implicated in Parkinson’s disease.

The new method uses a virus commonly employed by researchers to deliver DNA to brain cells. When the virus enters PV+ cells, Cre causes the tag to fluoresce. The antibodies were then used to detect the tag and pull the PV+ nuclei away from the others.

“The technique turned out to be really specific, really efficient,” Alyssa Lawler, PhD candidate at CMU, added, and noted that it can be adapted to other mouse models that use the Cre protein.

“Oxygen-sensing pathways have been implicated in other, earlier aspects of Parkinson’s disease, but not previously in PV+ cells,” Lawler said. These pathways are involved in both protecting and killing cells during neurodegeneration.

“Applying this technology to GPe PV+ neurons in a mouse model of Parkinson’s disease, we discovered evidence for upregulation of the oxygen homeostasis maintaining pathway involving Hif2a. These results provide new insight into how neuron subtypes outside the substantia nigra pars compacta (SNpc) may be compensating at a molecular level for differences in the motor production neural circuit during the progression of Parkinson’s disease,” according to the researchers.

The team noted that the datasets from their study are part of a larger effort to build machine learning models that will help researchers interpret disease mechanisms by looking at how particular DNA sequences respond to different conditions across types of cells.

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

Part of the disease process of Parkinson’s process develops as cells are destroyed in certain parts of the brain stem, particularly the crescent-shaped cell mass known as the substantia nigra. Nerve cells in the substantia nigra send out fibers to tissue located on both sides of the brain. There the cells release essential neurotransmitters that help control movement and coordination. These results provide new insight into how neuron subtypes outside the
substantia nigra may be compensating at a molecular level for differences in the motor production neural circuit during the progression of Parkinson’s disease.

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