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Neuroscientists find two distinct cell populations in the striatum are affected differently by Huntington's disease. They believe neurodegeneration of one of these populations leads to motor impairments, while damage to the other population, located in a structure called the striosome, may account for the mood disorders that are often see in the early stages of the disease. 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. 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. "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," says Ann Graybiel, an MIT Institute Professor, a member of MIT's McGovern Institute for Brain Research, and one of the senior authors of the study. 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. This kind of analysis could also shed light on other brain disorders that affect the striatum, such as Parkinson's disease and autism spectrum disorder, the researchers say. 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 Nature Communications. Neuron vulnerability Huntington's disease leads to degeneration of brain structures called the basal ganglia, which are responsible for control of movement and also play roles in other behaviors, as well as emotions. For many years, Graybiel has been studying the striatum, a part of the basal ganglia that is involved in making decisions that require evaluating the outcomes of a particular action. Many years ago, Graybiel discovered that the striatum is divided into striosomes, which are clusters of neurons, and the matrix, which surrounds the striosomes. She has also shown that 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 deal of degeneration. 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. To further explore the connections between the striatum and the mood and motor effects of Huntington's, Graybiel teamed up with Kellis and Heiman to study the gene expression patterns of striosomal and matrix cells. To do that, the researchers used single-cell RNA sequencing to analyze human brain samples and brain tissue from 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, 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. "Overall, the distinction between striosomes and matrix becomes really blurry," Graybiel says. Striosomal disorders 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. Later on, degeneration of the matrix neurons likely contributes to the decline of motor function, the researchers say. In future work, the researchers hope to explore how degeneration or abnormal gene expression in the striosomes may contribute to other brain disorders. 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. 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 says. 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.

Emalex Biosciences closed an upsized and oversubscribed Series D funding round Thursday, counting $250 million in earnings, much of which will bankroll a Phase III trial of ecopipam for Tourette syndrome. The funding round was led by Bain Capital Life Sciences. Paragon Biosciences, which founded Emalex in 2018, participated in the financing push alongside Valor Equity Partners and Fidelity Management & Research Company. In a statement, Emalex founder and Paragon CEO Jeff Aronin said that the Chicago-based neuroscience biotech was created specifically to address neurological conditions with high unmet need, like Tourette Syndrome. He added that Emalex recognizes “that drug development for neurologic conditions is exceptionally difficult and few companies are willing to invest in bringing new options to these patients.” With an enrollment target of over 220 patients across some 90 sites, Emalex is aiming for the largest Tourette trial ever conducted in North America. The Phase III study will assess the company’s ecopipam, a first-in-class investigational compound that disrupts the interaction of the neurotransmitter dopamine with the D1 receptor. Current therapies for Tourette target the D2 family of dopamine receptors. Ecopipam targets the D1 family, the super-sensitivity of which has been named in recent studies as a potential contributor to Tourette tics. The Phase IIb D1AMOND clinical trial confirmed ecopipam’s mode of action, showing that treatment with the candidate led to reduced motor and phonic tics as compared with placebo. The investigational drug was also well-tolerated, with the most common side effects being headache, fatigue and somnolence. There was no evidence of movement-related or metabolic adverse events. The FDA has granted ecopipam the Orphan Drug and Fast Track designations. Big Bucks in Brain Diseases Emalex’s oversubscribed financing round is only the latest development in the high-value neuroscience therapeutic space. In early October, Neumora Therapeutics raised $112 million in its Series B financing round to help it develop its neuroscience portfolio further. In particular, the company plans on using the proceeds to advance its lead candidate NMRA-140, a kappa opioid receptor antagonist for major depressive disorder. The money will also be channeled into Neumora’s other precision medicine programs for neuropsychiatric diseases. The company had previously raised $500 million in 2021. Soon after Neumora’s payday, Astellas put forth $50 million in a strategic equity investment and licensing deal, acquiring 15% of Taysha Gene Therapies. The agreement gives Astellas the exclusive option to license Taysha’s TSHA-102, a gene therapy for the severe genetic neurodevelopmental disorder Rett syndrome. The deal also includes TSHA-120, also a gene therapy under investigation for giant axonal neuropathy.

In a leap forward for diabetes research, researchers reveal that the feel-good hormone, dopamine, regulates insulin secretion through a heteromeric complex of receptors, thereby providing new targets for antidiabetic medication and therapy. The study is the first to elucidate the mechanism behind dopamine's down-regulation of insulin secretion. In a leap forward for diabetes research, Tokyo Tech researchers reveal that the 'feel-good hormone,' dopamine, regulates insulin secretion through a heteromeric complex of receptors, thereby providing new targets for antidiabetic medication and therapy. The study is the first to elucidate the mechanism behind dopamine's down-regulation of insulin secretion. Diabetes is a lifelong, chronic health condition caused by abnormalities in the body's production and use of the hormone insulin. Research has shown that the feel-good hormone, dopamine (DA), plays a key role in how the body regulates the production of insulin. Typically, insulin is secreted by cells in the pancreas called 'beta-cells,' in response to glucose -- a process that is aptly called 'glucose-stimulated insulin secretion (GSIS). DA negatively regulates GSIS, leading to transient changes in the body's levels of insulins. But the mechanism behind this regulation was unknown, until now. Recently, a team led by researchers from Tokyo Institute of Technology (Tokyo Tech) uncovered the precise mechanism through which DA regulates insulin secretions. Using a technique called "total internal reflection fluorescence microscopy," they were able to reveal that DA "receptors" -- proteins on cells that DA can bind to -- called D1 and D2, act in concert to achieve the transient regulation of insulin. "We found that D1 receptor antagonists -- drugs that block D1 receptors from activation -- decreased the dopamine-mediated inhibition of insulin secretion. We also saw that overexpression of only D2 receptors on beta cells exerted an inhibitory and toxic effect and abolished insulin secretion in beta-cells. This gave us a clue to the mechanism of down-regulation," explains Prof. Shoen Kume of Tokyo Tech, who led the study. The research team then performed further experiments called "proximity ligation" and "Western blot assays" to study the receptors further. They found that D1 and D2 bound to each other to form a complex called a "heteromer." When activated by DA, this heteromer transiently inhibited insulin secretion. They also saw that when D1 and D2 were co-expressed on beta-cells, the cells were able to bypass the toxic effects of D2 overexpression. Dr. Kume says, "From these findings it can be concluded that D1 modulates D2 signaling to protect beta-cells from the harmful effects of DA. This study greatly improves our understanding of DA signaling in diabetes." Understanding the mechanism of DA signaling in the regulation of insulin secretion is sure to provide new therapeutic targets for the prevention, treatment, and management of diabetes.