Researchers Explore Gene Regulatory Pathways and Neurological Disease

Mary Stroka
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New tool may help diagnose and treat Parkinson's disease in early stages
New tool may help diagnose and treat Parkinson’s disease in early stages
Study results provide new insight into how neuron subtypes outside the substantia nigra pars compacta may be compensating at a molecular level for differences in the motor production neural circuit during the progression of Parkinson’s disease.

To better identify and understand the gene regulatory pathways tied to neurological disease, researchers used Cre-Specific Nuclear Anchored Independent Labeling (cSNAIL), an enhanced, virus-based approach to isolate cells’ nuclei, to perform assessments in mice. The researchers found “GPe PV+ neuron-specific gene expression changes that suggested increased Hypoxia-inducible factor 2 alpha (Hif2a) signaling.” The findings were reported in The Journal of Neuroscience.

Using cSNAIL, researchers assessed the cell type-specific transcriptomic and epigenetic effects of dopamine depletion on PV+ and PV- cells within three brain regions of male and female mice: GPe, striatum, and cortex. The researchers also used INTACT system with modifications.

The heterozygous and transgenic mice were injected with adeno-associated viruses (AAV) and underwent dopamine depletion surgery.

After staining, imaging and dissecting, nuclei were extracted from tissue and genetic analysis began.

The researchers identified “a transcriptional regulatory network mediated by the neuroprotective factor Hif2a as underlying neural circuit differences in response to dopamine depletion.”

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GPe PV+ neurons were the only cell population with notable gene expression changes after dopamine depletion out of 6 cell populations.

“The evidence strongly supports an increase in HIF transcription factor activity in GPe PV+ neurons upon dopamine depletion,” the authors stated. “In the future, cSNAIL could be paired with protein assays to determine the precise [hypoxia-inducible factor] (HIF) protein expression levels, cellular localizations, and DNA binding events in GPe PV+ neurons in dopamine depletion.”

Reference

Lawler AJ, Brown AR, Bouchard RS, et al. Cell type-specific oxidative stress genomic signatures in the globus pallidus of dopamine depleted mice. J Neurosci. 2020 Nov 10:JN-RM-1634-20. doi:10.1523/JNEUROSCI.1634-20.2020