Huntington’s disease is a rare genetic disorder that causes progressive destruction (degeneration) of nerve cells in the brain. In patients with Huntington’s disease, striatal projection neurons (SPNs) gradually degenerate, contributing to the patient’s loss of motor control. This is one of the key features of this disease.
It is well established that indirect pathway SPNs are susceptible to neurodegeneration and transcriptomic disturbances. Still, less is known about how the striosome matrix axis is violated in HD relative to the canonical axis.
Neuroscientists at MIT have established that Huntington’s disease differentially affects two different cell groups in the striatum. They hypothesize that movement disorders result from neurodegeneration in one of these populations. Still, the mood disturbances frequently observed in the early stages of disease can be caused by damage to other populations found in structures called striosomes.
Scientists used single-cell RNA sequencing to analyze genes expressed in mouse models of Huntington’s disease and in postmortem brain samples from Huntington’s disease patients. They found that striosome cells and another structure, the matrix, began to lose their characteristics as the disease progressed.
Scientists “This analysis may also shed light on other brain disorders that affect the striatum, such as Parkinson’s disease and autism spectrum disorders.”
Neurons in the striatum can be classified as D1 or D2 neurons. D1 neurons play a role in the ‘go’ pathway that initiates behavior and D2 neurons play a role in the ‘no-go’ pathway that stops behavior. Both striosomes and matrices are home to D1 and D2 neurons.
Striosomal neurons are more susceptible to Huntington’s disease than matrix neurons, upon examination of RNA expression in each type of cell. Moreover, D2 neurons are more susceptible than her D1 neurons within striosomes.
Scientists also show that in Huntington’s disease, these four major cell types begin to lose their distinguishing molecular identities, making them more difficult to distinguish from each other. In other words, the distinction between striosomes and matrices blurs, scientists say.
Ann Greybeel, MIT Lab professor and member of MIT’s McGovern Brain Institute, said: “This finding suggests that damage to striosomes, known to be involved in mood regulation, may be responsible for the mood disturbances that strike Huntington’s patients in the early stages of the disease. Subsequent degeneration of matrix neurons may contribute to decreased motor function.”
Scientists look forward to investigating how striosome degeneration or aberrant gene expression contributes to other brain disorders.
Graybeer says: “There are many disorders that are probably striatum-related, and we are currently working to understand how they all fit together, in part through transcriptomics.”
Journal reference:
- Matsushima, A., Pineda, SS, Crittenden, JR et al. Transcriptional vulnerability of striatal neurons in human and rodent models of Huntington’s disease. Nat Commun 14, 282 (2023). DOI: 10.1038/s41467-022-35752-x
