Transcriptional vulnerabilities of striatal neurons in human and rodent models of Huntington’s disease
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s41467-022-35752-x.pdf
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Published version
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4.1 MB
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Checksum (MD5)
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Author(s)
Matsushima, Ayano
Pineda, Sergio Sebastian
Crittenden, Jill R
Lee, Hyeseung
Galani, Kyriakitsa
Mantero, Julio
Tombaugh, Geoffrey
Kellis, Manolis
Heiman, Myriam
Graybiel, Ann M
Date Issued
January 17, 2023
Journal
Nature Communications
Publisher
Springer Science and Business Media LLC
Citation
Matsushima, Ayano, Pineda, Sergio Sebastian, Crittenden, Jill R, Lee, Hyeseung, Galani, Kyriakitsa et al. 2023. "Transcriptional vulnerabilities of striatal neurons in human and rodent models of Huntington’s disease." Nature Communications, 14 (1).
Version
Final published version
Abstract
AbstractStriatal 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.
MIT Department
Massachusetts Institute of Technology. Department of Brain and Cognitive Sciences
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Creative Commons Attribution 4.0 International license
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DOI of Published Version
https://doi.org/10.1038/s41467-022-35752-x
