MIT researcher on new brain study: 'We’re working to understand how all of this could fit together'

Researchers at the Massachusetts Institute of Technology have identified two distinct cell populations in the brain that are affected differently by Huntington’s disease, which could help lead to new treatments that target specific cells within the brain, an MIT news release said.

The striatum is a part of the brain that is involved in making decisions that require evaluating the outcomes of a particular action, MIT said. It is also responsible for control of movement and plays roles in other behaviors, as well as emotions. In patients with Huntington’s disease, neurons in the striatum are among the hardest hit, contributing to patients’ loss of motor control, which is one of the major hallmarks of the disease.

The researchers used single-cell RNA sequencing to analyze genes expressed in mouse models of Huntington’s disease and postmortem brain samples from Huntington’s patients. They found that cells of the striosomes and another structure, the matrix, begin to lose their distinguishing features as the disease progresses. Striosomes are structures in the brain that regulate mood, and damage to them may account for the mood disorders often seen in the early stages of the disease. The analysis of RNA expression in each of the cell types 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.

“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,” said Ann Graybiel, an MIT professor and one of the senior authors of the study. Myriam Heiman, an associate professor in MIT’s Department of Brain and Cognitive Sciences and a member of The Picower Institute for Learning and Memory, and Manolis Kellis, a professor of computer science in MIT’s Computer Science and Artificial Intelligence Laboratory (CSAIL) and a member of the Broad Institute of MIT and Harvard, are also senior authors of the study.

Ayano Matsushima, a McGovern Institute research scientist, and Sergio Sebastian Pineda, an MIT graduate student, are the lead authors of the paper, which appears in the publication Nature Communications.

The researchers believe that neurodegeneration of one of the cell populations leads to motor impairments, while damage to the other population may account for mood disorders. In future work, the researchers hope to explore how degeneration or abnormal gene expression in the striosomes may contribute to other brain disorders. Overactivity of striosomes can lead to the development of repetitive behaviors such as those seen in autism, obsessive-compulsive disorder, and Tourette’s syndrome. Additionally, many striosome neurons project to the part of the brain that is most affected by Parkinson’s disease (the substantia nigra, which produces most of the brain’s dopamine).

“There are many, many disorders that probably involve the striatum, and now, partly through transcriptomics, we’re working to understand how all of this could fit together,” Graybiel said. 

The findings could shed light on other brain disorders that affect the striatum, such as Parkinson’s disease and autism spectrum disorder. 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, the Kristin R. Pressman and Jessica J. Pourian ’13 Fund, and Robert Buxton.