Single-nucleus multiomic profiling of the aging mouse substantia nigra reveals conserved gene alterations linked to Parkinson's disease
- Kangli Wang1,
- Weikun Xia1,
- Yingli Gu1,
- Songpeng Zu1,
- Qian Yang2,
- Maria Luisa Amaral1,
- Yaozhi Wang1,
- Allen Wang2,
- Xiang-Dong Fu3,
- William C. Mobley4 and
- Bing Ren1,2,5,6
- 1Department of Cellular and Molecular Medicine, University of California San Diego, School of Medicine, La Jolla, California 92093, USA;
- 2Center for Epigenomics, University of California San Diego, School of Medicine, La Jolla, California 92093, USA;
- 3Westlake Laboratory of Life Sciences and Biomedicine, School of Life Sciences, Westlake University, Hangzhou, Zhejiang 310024, China;
- 4Department of Neuroscience, University of California San Diego, La Jolla, California 92093, USA
Abstract
Parkinson's disease (PD) is a prevalent neurodegenerative disorder predominantly affecting individuals over 60. Its motor symptoms stem from the deterioration of dopaminergic neurons within the substantia nigra. Despite aging being a significant risk factor, the specific mechanisms linking aging and PD pathology remain unclear. Leveraging advancements in single-cell genomics, this study utilizes single-nucleus multiome sequencing to capture transcriptomic and epigenetic profiles from 40,125 cells across the lifespan of the mouse substantia nigra. Our analysis pinpoints age-associated changes at a cell type–specific level, revealing a subset of genes that increasingly express with age and are enriched in PD-related pathways, notably in oligodendrocytes at late aging stages. Integration with five public PD single-cell RNA-seq data sets highlights 85 genes consistently differentially expressed with aging and PD. Key genes such as Hsp90aa1 and Hsp90ab1 are upregulated at late aging stages in oligodendrocytes, microglia, and glutamatergic neurons. Additionally, Apoe in microglia and genes related to protein folding in oligodendrocytes are upregulated at late aging stages, whereas genes involved in myelination are downregulated at early aging stages in oligodendrocyte. Our multiomic atlas underscores the substantial regulatory network changes during aging that may predispose to PD, providing valuable insights for furthering understanding of PD pathogenesis and potential therapeutic targets.
Footnotes
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[Supplemental material is available for this article.]
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Article published online before print. Article, supplemental material, and publication date are at https://www.genome.org/cgi/doi/10.1101/gr.281113.125.
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Freely available online through the Genome Research Open Access option.
- Received June 23, 2025.
- Accepted March 2, 2026.
This article, published in Genome Research, is available under a Creative Commons License (Attribution-NonCommercial 4.0 International), as described at http://creativecommons.org/licenses/by-nc/4.0/.
