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A single-cell atlas of the human substantia nigra reveals cell-specific pathways associated with neurological disorders

Author

Listed:
  • Devika Agarwal

    (University of Oxford
    University of Oxford)

  • Cynthia Sandor

    (Cardiff University)

  • Viola Volpato

    (Cardiff University)

  • Tara M. Caffrey

    (University of Oxford
    University of British Columbia)

  • Jimena Monzón-Sandoval

    (Cardiff University)

  • Rory Bowden

    (Wellcome Trust Centre for Human Genetics)

  • Javier Alegre-Abarrategui

    (University of Oxford
    University of Oxford
    Imperial College London)

  • Richard Wade-Martins

    (University of Oxford)

  • Caleb Webber

    (University of Oxford
    Cardiff University)

Abstract

We describe a human single-nuclei transcriptomic atlas for the substantia nigra (SN), generated by sequencing approximately 17,000 nuclei from matched cortical and SN samples. We show that the common genetic risk for Parkinson’s disease (PD) is associated with dopaminergic neuron (DaN)-specific gene expression, including mitochondrial functioning, protein folding and ubiquitination pathways. We identify a distinct cell type association between PD risk and oligodendrocyte-specific gene expression. Unlike Alzheimer’s disease (AD), we find no association between PD risk and microglia or astrocytes, suggesting that neuroinflammation plays a less causal role in PD than AD. Beyond PD, we find associations between SN DaNs and GABAergic neuron gene expression and multiple neuropsychiatric disorders. Conditional analysis reveals that distinct neuropsychiatric disorders associate with distinct sets of neuron-specific genes but converge onto shared loci within oligodendrocytes and oligodendrocyte precursors. This atlas guides our aetiological understanding by associating SN cell type expression profiles with specific disease risk.

Suggested Citation

  • Devika Agarwal & Cynthia Sandor & Viola Volpato & Tara M. Caffrey & Jimena Monzón-Sandoval & Rory Bowden & Javier Alegre-Abarrategui & Richard Wade-Martins & Caleb Webber, 2020. "A single-cell atlas of the human substantia nigra reveals cell-specific pathways associated with neurological disorders," Nature Communications, Nature, vol. 11(1), pages 1-11, December.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-17876-0
    DOI: 10.1038/s41467-020-17876-0
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    Cited by:

    1. Julong Wei & Tova Y. Lambert & Aditi Valada & Nikhil Patel & Kellie Walker & Jayna Lenders & Carl J. Schmidt & Marina Iskhakova & Adnan Alazizi & Henriette Mair-Meijers & Deborah C. Mash & Francesca L, 2023. "Single nucleus transcriptomics of ventral midbrain identifies glial activation associated with chronic opioid use disorder," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
    2. Lei Tang & Nana Xu & Mengyao Huang & Wei Yi & Xuan Sang & Mingting Shao & Ye Li & Zhao-zhe Hao & Ruifeng Liu & Yuhui Shen & Feng Yue & Xialin Liu & Chuan Xu & Sheng Liu, 2023. "A primate nigrostriatal atlas of neuronal vulnerability and resilience in a model of Parkinson’s disease," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
    3. Rongbo Shen & Lin Liu & Zihan Wu & Ying Zhang & Zhiyuan Yuan & Junfu Guo & Fan Yang & Chao Zhang & Bichao Chen & Wanwan Feng & Chao Liu & Jing Guo & Guozhen Fan & Yong Zhang & Yuxiang Li & Xun Xu & Ji, 2022. "Spatial-ID: a cell typing method for spatially resolved transcriptomics via transfer learning and spatial embedding," Nature Communications, Nature, vol. 13(1), pages 1-17, December.

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