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Parkinson's Disease Described at Single-cell Epigenetic & Transcriptomic Level

By Stuart P. Atkinson, Ph.D.

June 12, 2024

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Introduction: How Does Aging Impact Gene Regulation and Expression in the Brain?

Although a range of studies have identified multiple environmental risk factors and a swathe of genetic components, advanced age represents the primary risk factor (Hindle, 2010) influencing the development of Parkinson's disease. The pathogenesis of this unfortunately common disorder involves the degeneration of dopaminergic neurons in the substantia nigra, which prompts debilitating neurological, cognitive, and motor symptoms.

Recent single-cell transcriptomic-based research has provided evidence for a somewhat surprising role of midbrain oligodendrocytes in Parkinson's disease development (Agarwal et al., Bryois et al., Reynolds et al., and Smajic et al.); however, we still understand little regarding the mechanisms that induce alterations in gene expression and the gene regulatory landscape of cells within the brain during the aging process and how these mechanisms differ in age-related neurodegenerative processes. How can we illuminate the mechanisms behind age-related neurodegeneration?

Researchers guided by Yoshiaki Tanaka (University of Montreal) and Yoon-Seong Kim (Rutgers-Robert Wood Johnson Medical School) sought to answer this question by simultaneously assessing gene expression and chromatin accessibility profiles in single-nuclei isolated from frozen, post-mortem midbrain samples from young (9 donors; mean, 24 y/o) and aged (8 donors; mean, 75 y/o) donors with no neurological disease and similar samples from Parkinson's disease donors (14 donors; mean, 81 y/o). Their illuminating study, reported recently in Nature Aging, describes how aging and Parkinson's disease differentially impact gene regulation/expression in distinct cell types in the midbrain and underscores how disease-associated oligodendrocytes may significantly contribute to neurodegeneration (Adams and Song et al.).

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The Power of Single-Cell Transcriptomic and Epigenetic Profiling

Adams and Song et al. applied paired single-nuclei RNA-sequencing (snRNA-seq) and single-nuclei assay for transposase-accessible chromatin with sequencing (snATAC-seq) to generate joint single-cell transcriptomic and chromatin accessibility profiles of the same single-cells from young donors, old donors, and donors with Parkinson's disease. Overall, they analyzed nearly 70,000 high-quality nuclei from the 31 donors, which supported the classification of nuclei into seven major cell types after interrogation of gene expression patterns of known cell type markers - neurons, oligodendrocytes, astrocytes, microglia, oligodendrocyte precursor cells, endothelial cells, and peripheral immune cells/T cells.

At first glance, the data provided evidence for only slight variations in chromatin accessibility profiles between groups (a comparable result to a previous snATAC-seq study in Alzheimer's disease; Morabito et al.). While gene expression patterns of cell type-specific genes correlated with promoter-proximal chromatin accessibility profiles, differential gene expression within cell types during aging or Parkinson's disease development did not. This result suggested that interactions between distal DNA elements (such as enhancers) may instead influence differential gene expression during aging and Parkinson's disease development, which the team subsequently inferred from paired single-nuclei transcriptomic and chromatin accessibility profiles from the same nuclei by applying a previously described analytical framework (Ma et al.). The resultant data confirmed that altered chromatin accessibility at distal enhancers drove the differences in gene expression profiles between the groups; furthermore, these cell-type-specific chromatin regions identified in Parkinson's disease samples contained single-nucleotide polymorphisms linked to neurodegenerative disease development.

At the cell level, glial cell types all displayed a degree of change with normal aging; however, the authors observed additional disease-associated alterations to oligodendrocytes and microglia. Indeed, they identified a Parkinson's disease-associated subset of oligodendrocytes that may drive pathogenesis; however, they also observed the retention of a large number of oligodendrocytes with a typical transcriptomic profile, which suggests that a few highly dysregulated cells may drive primary disease-associated processes. At the gene level, the team identified a set of genes that associated with Parkinson's disease development but not normal aging (including QDPR and SELENOP) and those that became altered during normal aging but became more severely affected in Parkinson's disease. This second set of genes included CARNS1, which encodes the carnosine synthase 1 protein that confers protective effects in various neurological conditions, including PD (Hipkiss, 2018 and Kubota et al.). Overall, the expression levels and the number of CARNS1-expressing oligodendrocytes displayed an incremental decrease during aging and Parkinson's disease development. Overall, the identified genes may represent a source of risk inherent to the aging process in that they may predispose healthy cells to develop a neurodegenerative disease-associated phenotype.

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Single-Cell Transcriptomic and Epigenetic Profiling: The Way Forward for Neurodegenerative Disease Studies?

Overall, these illuminating findings, revealed by cutting-edge single-cell transcriptome and epigenome profiling techniques, underscore the importance of midbrain oligodendrocytes to Parkinson's disease development and define potential cell-type-specific regulatory networks underpinning normal and disease-associated processes. Paired single-cell transcriptomic and epigenetic profiling may represent the way forward for Parkinson's disease studies but also apply to a range of additional conditions/disorders. Subsequent research in this area may aim to "fill in the gaps" between the age groups employed to understand more about how transcriptomic and epigenetic profiles and cell states slowly shift during aging. Additionally, the authors of this study hope that expanding their research into different brain regions will contribute to constructing a "brain-wide atlas" describing normal human aging and neurodegeneration.

For more on how single-cell transcriptomic and epigenetic profiling illuminates age-related neurodegeneration, head over to Nature Aging, March 2024.

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About the author

Stuart P. Atkinson, Ph.D.

Stuart was born and grew up in the idyllic town of Lanark (Scotland). He later studied biochemistry at the University of Strathclyde in Glasgow (Scotland) before gaining his Ph.D. in medical oncology; his thesis described the epigenetic regulation of the telomerase gene promoters in cancer cells. Following Post-doctoral stays in Newcastle (England) and Valencia (Spain) where his varied research aims included the exploration of epigenetics in embryonic and induced pluripotent stem cells, Stuart moved into project management and scientific writing/editing where his current interests include polymer chemistry, cancer research, regenerative medicine, and epigenetics. While not glued to his laptop, Stuart enjoys exploring the Spanish mountains and coastlines (and everywhere in between) and the food and drink that it provides!

Contact Stuart on Twitter with any questions

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