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Single-Cell Parkinson's Disease Study Reveals Dopamine Neuron Cell Type-Specific Perturbations

NEW YORK – By analyzing single-cell transcriptomic data of dopaminergic neurons from in vitro models of Parkinson's disease, researchers in the UK and South Korea have identified multiple neuronal subtypes with transcriptionally distinct profiles and differential sensitivities to stress.

In a paper published on Tuesday in Cell Reports, the researchers described their study of induced pluripotent stem cell (iPSC)-derived neurons to elucidate how gene expression changes in response to cytotoxic and genetic stressors. They validated their dopamine in vitro models by showing robust expression of Parkinson's disease GWAS genes and overlap with postmortem adult substantia nigra neurons. In addition, using isogenic SNCA-A53Tmutants, they found perturbations in glycolysis, cholesterol metabolism, synaptic signaling, and ubiquitin-proteasomal degradation. 

Importantly, the investigators also found that stress signatures were ameliorated through the use of felodipine, a US Food and Drug Administration-approved drug to treat high blood pressure.

"Overall, our study reveals cell type-specific perturbations in human dopamine neurons, which will further our understanding of [Parkinson's disease] and have implications for cell replacement therapies," the authors wrote.

Parkinson's disease is characterized by the loss of dopamine neurons in the substantia nigra and by the accumulation of protein aggregates in the surviving neurons that are composed primarily of alpha-synuclein encoded by the SNCA gene, the researchers noted. The SNCA-A53T mutation was the first genetic evidence of Parkinson's disease ever discovered. The challenge is to understand the mechanism by which genetic mutations influence Parkinson's pathology, and iPSC disease modeling allows for such analysis of human neurons in vitro. Recent reports have shown that such models have a high degree of heterogeneity and cellular variability, which can result in heterogeneous populations of poorly characterized cells. To address this issue, the researchers undertook a single-cell transcriptomic study using droplet-based single-cell RNA sequencing (scRNA-seq) to characterize the composition and cell type-specific response of more than 15,000 in vitro human dopamine neurons to genetic and cytotoxic stress at single-cell resolution.

For example, they identified the dopamine DAn1 and DAn2 neurons as the most mature dopaminergic subtypes and found that DAn3 neurons expressed some genes usually associated with glutamatergic and GABAergic identity. Interestingly, the researchers also observed the expression of serotonergic markers in DAn2 neurons.

In one validation experiment, they compared data from the neurons they derived in culture with a single-cell transcriptomics dataset from postmortem brain samples of seven control patients. They found overlapping clusters between the datasets, in particular for DAn1 neurons, suggesting that iPSC-derived dopamine neurons are representative of corresponding human adult neurons.

The researchers also explored the functional annotation of gene expression profiles across the different cell types identified in their cultures. Importantly, they found distinct transcriptomic profiles across different cell types. Populations classified as progenitors displayed upregulation of genes associated with translation and protein processing and downregulation of genes involved in synaptic function and neuronal differentiation. In DAn1 neurons, the top differentially expressed genes included those associated with dopamine neuronal lineage and with Parkinson's disease, such as SNCA.

In another experiment, the researchers confirmed the expression of 63 out of 67 previously described Parkinson's-associated GWAS genes using their in vitro model. Importantly, the expression of some GWAS genes was different across cell types. For example, in addition to SNCA and MAPT, they found that expression of SYT4, SCN3A, ANK2, and ATP6V0A1 was significantly higher in DAn1 neurons, while the expression of PDLIM2 and CTSB was higher in the progenitor neuronal populations. These cell type-dependent expression dynamics suggested that some identified GWAS genes may be implicated at different stages of dopamine neuron development in the context of Parkinson's disease.

"Notably, the different responses of these cell types to toxic and genetic stressors highlight the importance of cell type specificity that can be captured only by single-cell readouts," the authors concluded. "These results align with recent observations that even closely related and morphologically indistinguishable neuronal cell types respond to perturbations via distinct molecular pathways."

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