Huntington Disease Compromises Striatal Neurons Differently

Huntington disease appears to affect 2 distinct cell populations in the striatum differently. According to a study published online in Nature Communications by neuroscientists at the Massachusetts Institute of Technology in Cambridge, Massachusetts, neurodegeneration in one of the affected populations may lead to motor impairments, and damage to the other may account for the mood disorders that often occur earlier in the disease.

To study connections between the striatum and mood and motor effects of Huntington disease, researchers focused on gene expression patterns of striosomal and matrix cells. They used single-cell RNA sequencing to analyze postmortem brain samples from patients with Huntington disease and brain tissue from two mouse models of Huntington disease.

Neurons in the striatum are classified as either D1 or D2 neurons, the research team explained. D1 neurons are involved in the pathway that initiates an action. D2 neurons are part of the pathway that suppresses an action. Both D1 and D2 neurons can be found within the striosomes and the matrix.

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Analysis of RNA expression revealed that striosomal neurons are harder hit by Huntington disease than matrix neurons. D2 neurons within the striosomes are more vulnerable than D1 neurons, researchers reported.

As the disease progresses, cells of striosomes and the matrix start to lose their distinguishing features, the study found.

“Overall, the distinction between striosomes and matrix becomes really blurry,” said corresponding author Ann Graybiel, PhD, professor and member of the Massachusetts Institute of Technology McGovern Institute for Brain Research.

The findings suggest that damage to the striosomes, which are known to be involved in regulating mood, may be responsible for the mood disorders that emerge earlier in Huntington disease patients, researchers explained. Degeneration of the matrix neurons likely contributes to motor function declines that occur later.

Researchers hope their mapping of the striatum and how it is affected by Huntington disease could help lead to new treatments that target specific cells within the brain.

References

Matsushima A, Pineda SS, Crittenden JR, et al. Transcriptional vulnerabilities of striatal neurons in human and rodent models of Huntington's disease. Nat Commun. Published online January 17, 2023. doi:10.1038/s41467-022-35752-x

Trafton A. How Huntington’s disease affects different neurons. News release. Massachusetts Institute of Technology; January 20, 2023. Accessed February 10, 2023.