In patients with Huntington’s disease, nerve cells in a part of the brain called the striatum are most affected. The degeneration of these neurons contributes to the patient’s loss of motor control, which is one of the main features of the disease.
MIT neuroscientists have now shown that two different groups of cells in the striatum are affected differently by Huntington’s disease. They believe that neurodegeneration of one of these groups leads to movement impairments, while damage to the other population, located in structures called stereosomes, may be responsible for the mood disturbances that often appear in the early stages of the disease.
“Ten years before a motor diagnosis, Huntington’s patients could have mood disorders, and one possibility is that stereoisomers may be involved in these disorders,” says Ann Graybel, MIT professor and fellow at MIT’s McGovern Brain Institute. research, and one of the study’s senior authors.
Using single-cell RNA sequencing to analyze genes expressed in mouse models of Huntington’s disease and postmortem brain samples from Huntington’s patients, the researchers found that cells of the stereosomes and another structure, the matrix, begin to lose their characteristic features as the disease progresses. The researchers hope that their mapping of the striatum and how it affects Huntington’s will help lead to new therapies that target specific cells within the brain.
Researchers say this type of analysis could also shed light on other brain disorders that affect the striatum, such as Parkinson’s disease and autism spectrum disorder.
Miriam Heymann, Associate Professor in MIT’s Department of Brain and Cognitive Sciences and member of the Bequewer Institute for Learning and Memory, and Manolis Kelis, Professor of Computer Science in MIT’s Computer Science and Artificial Intelligence Laboratory (CSAIL) and member of the Broad Institute at MIT and the University of Harvard is a senior author of the study. Ayano Matsushima, a research scientist at the McGovern Institute, and Sergio Sebastian Pineda, a graduate student at the Massachusetts Institute of Technology, are the lead authors of the paper, which appears in Nature Communications.
Huntington’s disease leads to degeneration of brain structures called basal ganglia, which are responsible for controlling movement and also play roles in other behaviors, as well as emotions. For many years, Graybiel has been studying the striatum, the part of the basal ganglia that is involved in making decisions that require evaluating the results of a particular action.
Several years ago, Graybel discovered that the striatum is divided into stereosomes, which are groups of neurons, and the matrix that surrounds corpuscles. They have also shown that stereosomes are essential for making decisions that require a troubling cost-benefit analysis.
In a 2007 study, Richard Voll of the University of Auckland discovered that in postmortem brain tissue from Huntington’s patients, stereosomes showed a significant amount of degeneration. Voll also found that while these patients were alive, many of them showed signs of mood disorders such as depression before their motor symptoms developed.
To further explore the connections between the striatum, mood, and motor effects of Huntington’s, Graybiel collaborated with Kellis and Heiman to study the gene expression patterns of somatic and matrix cells. To do this, the researchers used single-cell RNA sequencing to analyze human brain samples and brain tissue from two murine models of Huntington’s disease.
Within the striatum, neurons can be classified as either D1 or D2 cells. D1 neurons are involved in the “go” pathway, which initiates action, and D2 neurons are part of the “no-go” pathway, which suppresses action. Both D1 and D2 neurons can be found within the corpuscle and matrix.
Analysis of RNA expression in each of these cell types revealed that corpus callosum neurons are more frequently damaged than Huntington’s neurons than matrix neurons. Moreover, within the corpuscles, D2 neurons are more vulnerable than D1 neurons.
The researchers also found that these four major cell types begin to lose their specific molecular identities and become more difficult to distinguish from each other in Huntington’s disease. “In general, the distinction between array and matrix gets really blurry,” says Graybill.
The results suggest that damage to stereosomes, which are known to be involved in regulating mood, may be responsible for the mood disorders that affect Huntington’s patients in the early stages of the disease. Subsequently, degeneration of matrix neurons likely contributes to the deterioration of motor function, the researchers say.
In future work, the researchers hope to explore how degeneration or abnormal gene expression in the autosomes may contribute to other brain disorders.
Previous research has shown that excessive activity of stereosomes 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 stereosomes of Huntington’s brains also linked to autism.
In addition, many corpuscular neurons project to the part most affected by Parkinson’s disease (the substantia nigra, which produces most of the dopamine in the brain).
“There are many, many disorders that potentially involve the striatum, and now, in part through transcriptology, we’re working to understand how all of this might fit together,” says Graybill.
The research was funded by the Saks Kavanaugh Foundation, the CHDI Foundation, the National Institutes of Health, the Nancy Lurie Marks Family Foundation, the Simons Foundation, the JPB Foundation, and the Christine R. Robert Buxton.
Massachusetts Institute of Technology