Why are some neurons more vulnerable to Huntington’s disease?

A part of the brain called the striatum is most affected in people with Huntington’s disease. Degeneration of these neurons contributes to the patient’s loss of motor control, one of the main hallmarks of this disease.

Neuroscientists at MIT have shown that two different cell populations in the striatum are differentially affected by Huntington’s disease. They believe that neurodegeneration in one of these populations leads to movement disorders, but damage to other populations in structures called striosomes is responsible for the mood disturbances that are common in the early stages of disease. There is a possibility.

“As many as 10 years before a motor diagnosis, people with Huntington’s disease may experience mood disturbances, and striosomes may be involved in these,” said the MIT study, a member of the MIT McGovern Brain Institute. Tokoro Professor Ann Graybeer says: The study, and he is one of the senior authors of the study.

Using single-cell RNA sequencing to analyze genes expressed in mouse models of Huntington’s disease and in post-mortem brain samples from patients with Huntington’s disease, we found that striosomes and cells of another structure, the matrix, became more active as the disease progressed. It turns out that it begins to lose the characteristics of . .

Researchers hope that mapping the striatum and its effects on Huntington’s disease will lead to new treatments that target specific cells in the brain.

This kind of analysis could also shed light on other brain disorders that affect the striatum, such as Parkinson’s disease and autism spectrum disorders, the researchers say.

Myriam Heiman, associate professor in the Brain and Cognitive Sciences Division at MIT and member of the Picower Institute for Learning and Memory, and professor of computer science at MIT’s Computer Science and Artificial Intelligence Laboratory (CSAIL) and professor at MIT and Harvard. The Broad Institute is also a senior author on this study. Ayano Matsushima, a research scientist at the McGovern Institute, and Sergio Sebastian Pineda, a graduate student at MIT, are the lead authors of the paper. Nature Communications.

neuron vulnerability

Huntington’s disease causes degeneration of a brain structure called the basal ganglia. The basal ganglia are responsible for motor control and are involved in other behaviors and emotions. For many years, Greybeer has studied the striatum, the part of the basal ganglia involved in decision-making where the consequences of certain actions need to be evaluated.

Many years ago, Greybeer discovered that the striatum is divided into striosomes, clusters of neurons, and a matrix that surrounds the striosomes. She also showed that striosomes are necessary for making decisions that require anxiety-inducing cost-benefit analyses.

In a 2007 study, Richard Faull of the University of Auckland found that in postmortem brain tissue from Huntington’s disease patients, striosomes displayed considerable degeneration. Foul also found that while those patients were alive, many showed signs of mood disorders such as depression before motor symptoms appeared.

To further explore the relationship between the striatum and the mood and motor effects of Huntington’s disease, Graybiel collaborated with Kellis and Heiman to study gene expression patterns in striosomes and matrix cells. To do that, the researchers used single-cell RNA sequencing to analyze human brain samples and brain tissue from her two mouse models of Huntington’s disease.

Within the striatum, neurons can be classified as either D1 or D2 neurons. D1 neurons are involved in the ‘go’ pathway that initiates action, and D2 neurons are part of the ‘no-go’ pathway that inhibits action. Both D1 and D2 neurons reside within either striosomes or matrices.

Analysis of RNA expression in each of these cell types revealed that striosome neurons are more susceptible to Huntington’s disease than matrix neurons. Moreover, within striosomes, D2 neurons are more fragile than D1.

The researchers also found that in Huntington’s disease, these four major cell types begin to lose their identifying molecular identities, making them more difficult to distinguish from each other. “Overall, the distinction between striosomes and matrices becomes very blurred,” says Greybeer.

striosome disorder

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 disease patients in the early stages of the disease. Subsequently, degeneration of matrix neurons likely contributes to decreased motor function, researchers say.

In future studies, we hope to study how striosome degeneration or aberrant gene expression contributes to other brain disorders.

Previous studies have shown that excessive striosome activity 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 the researchers discovered was overexpressed in the striosomes in Huntington’s brain and is also associated with autism.

In addition, many striosome neurons project to the part of the brain most affected by Parkinson’s disease: the substantia nigra, which produces the majority of the brain’s dopamine.

“There are so many diseases that are probably related to the striatum, and we are currently working to understand how they all fit together, in part through transcriptomics,” says Graybiel. .

reference: Matsushima, A., Pineda SS, Crittenden JR, et al. Transcriptional vulnerability of striatal neurons in human and rodent models of Huntington’s disease. Nat Commune2023;14(1):282. Doi: 10.1038/s41467-022-35752-x

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