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Transcriptional vulnerabilities of striatal neurons in human and rodent models of Huntington’s disease

Author

Listed:
  • Ayano Matsushima

    (Massachusetts Institute of Technology
    Massachusetts Institute of Technology)

  • Sergio Sebastian Pineda

    (Massachusetts Institute of Technology
    Broad Institute of MIT and Harvard
    MIT
    MIT Computer Science and Artificial Intelligence Laboratory)

  • Jill R. Crittenden

    (Massachusetts Institute of Technology
    Massachusetts Institute of Technology)

  • Hyeseung Lee

    (Massachusetts Institute of Technology
    Broad Institute of MIT and Harvard)

  • Kyriakitsa Galani

    (Broad Institute of MIT and Harvard
    MIT Computer Science and Artificial Intelligence Laboratory)

  • Julio Mantero

    (Broad Institute of MIT and Harvard
    MIT Computer Science and Artificial Intelligence Laboratory)

  • Geoffrey Tombaugh

    (PyschoGenics Inc.)

  • Manolis Kellis

    (Broad Institute of MIT and Harvard
    MIT
    MIT Computer Science and Artificial Intelligence Laboratory)

  • Myriam Heiman

    (Massachusetts Institute of Technology
    Massachusetts Institute of Technology)

  • Ann M. Graybiel

    (Massachusetts Institute of Technology
    Massachusetts Institute of Technology)

Abstract

Striatal projection neurons (SPNs), which progressively degenerate in human patients with Huntington’s disease (HD), are classified along two axes: the canonical direct-indirect pathway division and the striosome-matrix compartmentation. It is well established that the indirect-pathway SPNs are susceptible to neurodegeneration and transcriptomic disturbances, but less is known about how the striosome-matrix axis is compromised in HD in relation to the canonical axis. Here we show, using single-nucleus RNA-sequencing data from male Grade 1 HD patient post-mortem brain samples and male zQ175 and R6/2 mouse models, that the two axes are multiplexed and differentially compromised in HD. In human HD, striosomal indirect-pathway SPNs are the most depleted SPN population. In mouse HD models, the transcriptomic distinctiveness of striosome-matrix SPNs is diminished more than that of direct-indirect pathway SPNs. Furthermore, the loss of striosome-matrix distinction is more prominent within indirect-pathway SPNs. These results open the possibility that the canonical direct-indirect pathway and striosome-matrix compartments are differentially compromised in late and early stages of disease progression, respectively, differentially contributing to the symptoms, thus calling for distinct therapeutic strategies.

Suggested Citation

  • Ayano Matsushima & Sergio Sebastian Pineda & Jill R. Crittenden & Hyeseung Lee & Kyriakitsa Galani & Julio Mantero & Geoffrey Tombaugh & Manolis Kellis & Myriam Heiman & Ann M. Graybiel, 2023. "Transcriptional vulnerabilities of striatal neurons in human and rodent models of Huntington’s disease," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-022-35752-x
    DOI: 10.1038/s41467-022-35752-x
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    References listed on IDEAS

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    1. Shahin Mohammadi & Jose Davila-Velderrain & Manolis Kellis, 2020. "A multiresolution framework to characterize single-cell state landscapes," Nature Communications, Nature, vol. 11(1), pages 1-14, December.
    2. Francisco J. Garcia & Na Sun & Hyeseung Lee & Brianna Godlewski & Hansruedi Mathys & Kyriaki Galani & Blake Zhou & Xueqiao Jiang & Ayesha P. Ng & Julio Mantero & Li-Huei Tsai & David A. Bennett & Must, 2022. "Single-cell dissection of the human brain vasculature," Nature, Nature, vol. 603(7903), pages 893-899, March.
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    Cited by:

    1. BaDoi N. Phan & Madelyn H. Ray & Xiangning Xue & Chen Fu & Robert J. Fenster & Stephen J. Kohut & Jack Bergman & Suzanne N. Haber & Kenneth M. McCullough & Madeline K. Fish & Jill R. Glausier & Qiao S, 2024. "Single nuclei transcriptomics in human and non-human primate striatum in opioid use disorder," Nature Communications, Nature, vol. 15(1), pages 1-19, December.

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