| First Author | Matsushima A | Year | 2023 |
| Journal | Nat Commun | Volume | 14 |
| Issue | 1 | Pages | 282 |
| PubMed ID | 36650127 | Mgi Jnum | J:339512 |
| Mgi Id | MGI:7427972 | Doi | 10.1038/s41467-022-35752-x |
| Citation | Matsushima A, et al. (2023) Transcriptional vulnerabilities of striatal neurons in human and rodent models of Huntington's disease. Nat Commun 14(1):282 |
| abstractText | 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. |
