Researchers identify a subtype of brain cells that die in Parkinson's patients

Researchers identify a subtype of brain cells that die in Parkinson’s patients
Quantification of DA subtype vulnerability to PD-associated degeneration. a, Volcano plot showing OR and FDR computed by MASC (Methods) for each of the 68 clusters identified in SNpc snRNA-seq analysis. Labeled clusters are those significantly (FDR-adjusted P < 0.05) increased or depleted in association with PD/LBD. Points and text are colored by major cell type: dark green, DA neurons; yellow, microglia/macrophages; purple, OPCs; light green, endothelial cells/pericytes; pink, astrocytes. b, OR estimate of ten dopaminergic subpopulations as identified by MASC. Center of bar corresponds to OR estimate obtained from MASC, width corresponds to 2.5× s.d. of OR estimate from MASC. Bars that cross zero (dotted line) not statistically significant (FDR-adjusted P > 0.05, n = 22,048 DA neurons sampled across ten PD/LBD donors and eight neurotypical donors). c, Left: disease enrichment score (Methods) overlaid onto a binned UMAP representation of integrative analysis of both PD/LBD and control DA neurons (n = 10 PD/LBD individuals and n = 8 neurotypical controls). Right: expression of selected genes used to validate subtype vulnerability plotted on UMAP representation of DA neurons. d, Representative images of triple-positive cells for a disease-resistant DA population (TH+/CALB1+/TMEM200A+) and a disease-vulnerable population (TH+/AGTR1+/SOX6+, bottom). White/black asterisks indicate neuromelanin-induced autofluorescence while white arrows show lipofuscin-induced autofluorescence; gray arrows indicate RNA puncta. Scale bars, 10 μm. e, Boxplot showing proportions of four DA populations across ten PD and ten control SNpc tissue donors, determined by counting smFISH images from the two staining procedures (3,258 and 2,081 DA neurons counted for first and second assay, respectively) described in d. Center line of the boxplot indicates the median value while upper and lower hinges indicate the first and third quartiles of data, respectively. Whisker distance between upper and lower hinges represent ≤1.5× interquartile range. All dots represent an individual case for each subtype as a fraction of total TH+ cells counted. +, positive for marker; −, negative for marker; NM, not measured; NS, not significant. *P < 0.05 (P = 0.041 for CALB1+/TMEM200A+/TH+ comparison, P = 0.028 for CALB1+/TMEM200A/TH+ comparison, P = 0.009 for CALB1+/TH+ comparison, P = 0.024 for SOX6+/AGTR1+/TH+ comparison, P = 0.28 for SOX6+/AGTR1/TH+ experiment and P = 0.015 for SOX6+/AGTR1/TH+ comparison; Wilcoxon rank-sum two-sided test; Methods). Credit: Nature Neuroscience (2022). DOI: 10.1038/s41593-022-01061-1

A team of researchers affiliated with several institutions in the U.S. has identified a subtype of brain cells that die in Parkinson's patients. In their study, published in the journal Nature Neuroscience, the group used a new RNA sequencing technique to analyze brain cells in the substantia nigra and then compared certain types they found in the brains of Parkinson's patients with unafflicted subjects to identify differences. Ernest Arenas, with the Karolinska Institutet in Sweden published a News & Views piece in the same journal issue outlining how single-cell study of brain cells is conducted and commenting on the work reported by the team on this new effort.

Parkinson's disease is a progressive neurodegenerative disease—patients experience balance problems, trouble speaking and tremors. There is no cure, but some drugs can reduce symptoms. Prior research has shown that the disease arises when nerve cells in the (located in the midbrain) deteriorate for unknown reasons. As a result, less dopamine is generated. As more of the cells cease functioning, symptoms worsen. In this new effort, the researchers took a closer look at the in the substantia nigra to find out which of them die in Parkinson's patients.

The researchers used a recently developed single-cell RNA technique that sequences individual cells in a given tissue sample. The researchers used it to determine which genes in cells in the substantia nigra were producing proteins and then categorized them into 10 subtypes.

They then obtained brain samples from 10 people who had had Parkinson's (or Lewy body dementia) at the time of their death. They performed the same type of RNA sequencing on all of the samples and also on multiple brain samples collected from unafflicted people post-mortem. They compared samples from both groups looking for differences and found one of the reduced brain cell subtypes in the Parkinson's patients, suggesting strongly that it is the most affected in people with Parkinson's.

More information: Tushar Kamath et al, Single-cell genomic profiling of human dopamine neurons identifies a population that selectively degenerates in Parkinson's disease, Nature Neuroscience (2022). DOI: 10.1038/s41593-022-01061-1

Ernest Arenas, Parkinson's disease in the single-cell era, Nature Neuroscience (2022). DOI: 10.1038/s41593-022-01069-7

Journal information: Nature Neuroscience

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