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

Ayano Matsushima, Sergio Sebastian Pineda, Jill R. Crittenden, Hyeseung Lee, Kyriakitsa Galani, Julio Mantero, Geoffrey Tombaugh, Manolis Kellis, Myriam Heiman and Ann M. Graybiel ()
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Ayano Matsushima: Massachusetts Institute of Technology
Sergio Sebastian Pineda: Massachusetts Institute of Technology
Jill R. Crittenden: Massachusetts Institute of Technology
Hyeseung Lee: Massachusetts Institute of Technology
Kyriakitsa Galani: Broad Institute of MIT and Harvard
Julio Mantero: Broad Institute of MIT and Harvard
Geoffrey Tombaugh: PyschoGenics Inc.
Manolis Kellis: Broad Institute of MIT and Harvard
Myriam Heiman: Massachusetts Institute of Technology
Ann M. Graybiel: Massachusetts Institute of Technology

Nature Communications, 2023, vol. 14, issue 1, 1-17

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-022-35752-x

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