How Huntington’s disease affects two distinct cell populations in the striatum

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"In patients with Huntington’s disease, neurons in a part of the brain called the striatum are among the hardest-hit. Degeneration of these neurons contributes to patients’ loss of motor control, which is one of the major hallmarks of the disease.

Neuroscientists ... have now shown that two distinct cell populations in the striatum are affected differently by Huntington’s disease. They believe that neurodegeneration of one of these populations leads to motor impairments, while damage to the other population, located in structures called striosomes, may account for the mood disorders that are often seen in the early stages of the disease.

“As many as 10 years ahead of the motor diagnosis, Huntington’s patients can experience mood disorders, and one possibility is that the striosomes might be involved in these,” ...
Using single-cell RNA sequencing to analyze the genes expressed in mouse models of Huntington’s disease and postmortem brain samples from Huntington’s patients, the researchers found that cells of the striosomes and another structure, the matrix, begin to lose their distinguishing features as the disease progresses.  ...
This kind of analysis could also shed light on other brain disorders that affect the striatum, such as Parkinson’s disease and autism spectrum disorder, the researchers say. ...
The researchers also found that these four major cell types begin to lose their identifying molecular identities and become more difficult to distinguish from one another in Huntington’s disease. “Overall, the distinction between striosomes and matrix becomes really blurry,” ...
Previous research has shown that overactivity of striosomes can lead to the development of repetitive behaviors such as those seen in autism, obsessive compulsive disorder, and Tourette’s syndrome. ..."

From the 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."

How Huntington’s disease affects different neurons | MIT News | Massachusetts Institute of Technology A new study identifies cells that are the most vulnerable within a brain structure involved in mood and movement.

Transcriptional vulnerabilities of striatal neurons in human and rodent models of Huntington’s disease (open access)

Fig. 1: Identification and characterization of human and rodent SPN cell-type-specific markers