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. 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. Huntington’s disease leads to degeneration of brain structures called the basal ganglia, which are responsible for control of movement and also In these structures there is the striatum, a part of the basal ganglia that is involved in making decisions that require evaluating the outcomes of a particular action. Neuroscientists at MIT 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 see in the early stages of the disease.
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. The researchers hope that their mapping of the striatum and how it is affected by Huntington’s could help lead to new treatments that target specific cells within the brain. According to scientists, this investigation could also shed light on other brain disorders that affect the striatum, such as Parkinson’s disease and autism spectrum disorder. The team, led by Dr. Graybiel, discovered that the striatum is divided into striosomes (clusters of neurons) and the matrix, which surrounds the striosomes. Striosomes are necessary for making decisions that require an anxiety-provoking cost-benefit analysis. In a 2007 study, Richard Faull of the University of Auckland discovered that in postmortem brain tissue from Huntington’s patients, the striosomes showed a great percentage of degeneration.
Dr. Faull also found that while those patients were alive, many of them had shown signs of mood disorders such as depression before their motor symptoms developed. Within the striatum, neurons can be classified as either D1 or D2 neurons. D1 neurons are involved in the “go” pathway, which initiates an action, and D2 neurons are part of the “no-go” pathway, which suppresses an action. D1 and D2 neurons can both be found within either the striosomes and the matrix. The analysis of RNA expression in each of these types of cells revealed that striosomal neurons are harder hit by Huntington’s than matrix neurons. Furthermore, within the striosomes, D2 neurons are more vulnerable than D1. 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. 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 strike Huntington’s patients in the early stages of the disease.
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. In this study, at least one of the genes that the researchers discovered was overexpressed in the striosomes of Huntington’s brains is also linked to autism. Striatum, howeever, is no the only brain area possibily affected by Huntington disease. Cerebellum is in the list, although ittle is known about cell type-specific responses of cerebellar neurons in this condition. Using the experimental HdhQ200 knock-in mice model, researchers found that mice had very mild behavioral abnormalities starting around 12 months of age that remained mild up to 18 months. By 9 months, they observed abundant Huntingtin-positive neuronal intranuclear inclusions in the striatum and cerebellum. Analysis of gene expression in cerebellar granuls, the main neuronal component of cerebellum, revealed that there are hundreds of genes related to glutamate network that showed altered expression.
A curious hallmark was that these cells seem to re-enter the cell cycle aberrantly, by expriming nuclear proteins like Cbx transcription factors and cyclin D1, a typical driver of cellular replication. Mitosis in not contemplated for mature neurons, since they are a “terminally committed” cell typology. Any attempt to re-enter the cell cycle would result in the so-called “mitotic catastrophe”, resulting ultimately in neuronal death. Therefore, like other neurological conditions esperimentally and clinically investigated, re-entering the cells cycle in cerebellar neurons could match for the moment the disease is progressing from the behavioral towrd the motor complicances.
- Edited by Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.
Bauer S et al. Acta Neuropathol Commun 2023 Jan 20; 11(1):17.
Matsushima A, Pineda SS et al. Nat Commun. 2023 Jan;14(1):282.
Singh-Bains MK, Mehrabi NF et al. Ann Neurol. 2019; 85:396–405.
Reiner A, Albin R et al. Proc Natl Acad Sci USA. 1988; 85:5733-37.
Dott. Gianfrancesco Cormaci
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