Huntington’s disease is a rare, inherited disease that causes the progressive breakdown (degeneration) of nerve cells in the brain. In patients with Huntington’s disease, striatal projection neurons (SPNs) gradually degenerate, contributing to the loss of motor control in patients, which is one of the key features of the disease.

It is well known that the indirect pathway SPNs are susceptible to neurodegeneration and transcriptomic disorders. Yet less is known about how the striosome-matrix axis is compromised to the canonical axis in HD.

Neuroscientists at MIT have now determined that Huntington’s disease has different effects on two different cell groups in the striatum. They hypothesize that motor impairments result from the neurodegeneration of one of these populations. Yet the mood abnormalities often seen in the early stages of the disease may be caused by damage to the other population, which is found in structures called striosomes.

Scientists used single-cell RNA sequencing to analyze the genes expressed in mouse models of HD and postmortem brain samples from HD patients. They found that the cells’ striosomes and another structure, the matrix, begin to lose their distinctive features as the disease progresses.

Scientists noted, “This analysis may also shed light on other brain disorders that affect the striatum, such as Parkinson’s disease and autism spectrum disorder.”

Neurons in the striatum can be categorized as D1 or D2 neurons. D1 neurons play a role in the “go” pathway, which initiates an action, while D2 neurons play a role in the “no-go” pathway, which stops an action. The striosomes and matrix are both home to D1 and D2 neurons.

Striosomal neurons are more severely affected by Huntington’s disease than matrix neurons, according to a study of RNA expression in each cell type. In addition, D2 neurons are more sensitive than D1 neurons in the striosomes.

Scientists also show that these four main cell types begin to lose their identifying molecular identity and become more difficult to tell apart in Huntington’s disease. In other words, the distinction between striosomes and matrix becomes blurry, scientists noted.

Ann Graybiel, a professor at the MIT Institute and a member of MIT’s McGovern Institute for Brain Research, said: “The findings suggest that damage to the striosomes, known to be involved in regulating mood, may be responsible for the mood disturbances that affect Huntington’s patients in the early stages of the disease. Later, degeneration of the matrix neurons likely contributes to the decline in motor function.”

Scientists look forward to exploring how degeneration or abnormal gene expression in the striosomes may contribute to other brain disorders.

Graybiel said, “There are loads of conditions that probably involve the striatum, and now, partly through transcriptomics, we’re trying to understand how this might all fit together.”

Magazine reference:

  1. Matsushima, A., Pineda, SS, Crittenden, JR et al. Transcriptional vulnerabilities of striatal neurons in human and rodent models of Huntington’s disease. Nat Commun 14, 282 (2023). DOI: 10.1038/s41467-022-35752-x