Huntington’s disease, a hereditary and fatal genetic disease, has long been considered a neuronal disease due to the permanent loss of motor neurons in the middle spines, the death of which over time is responsible for the clinical signs of the disease: involuntary movements, disorders coordination, cognitive decline, depression and psychosis.
However, a growing body of research, including a new study in the journal Cell reports, suggests that the disease may also stem from defects in glia, important support cells found in the brain. The new study expands our understanding of the mechanisms underlying disease and strengthens the potential for therapies that target glial cells.
Years of research in the laboratory of neurologist Steve Goldman, MD, Ph.D. at the University of Rochester Medical Center (URMC), have shown that the two populations of glial cells found in the brain – astrocytes and oligodendrocytes – are dysfunctional in Huntington’s disease, and can trigger much of the neuronal pathology seen in the disease. Goldman is co-director of the Center for Translational Neuromedicine at URMC and senior author of the new study. Glial cells play an essential role in maintaining the health of neurons and facilitating chemical signaling between nerve cells. In Huntington’s disease, glial cells are unable to perform these functions, leading to a breakdown in communication between neurons and, over time, cell death.
“Huntington’s disease is a complex disease that affects both neurons and supporting cells. To use an analogy, not only is the patient sick, but so are the doctor and nurse,” said Abdellatif Benraiss, Ph.D., associate research professor in the Department of Neurology at URMC and first author of the study. “While the loss of neurons gives rise to the symptoms and ultimate fatal nature of the disease, reversing glial dysfunction may give us the opportunity to intervene early in the course of the disease, keeping neurons alive. good health for longer and slowing the progression of the disease.”
The new study focuses on oligodendrocytes and identifies how deletion of a specific transcription gene called Tcf7l2 triggers a series of changes that impair the function of oligodendrocyte progenitor cells (OPCs). These cells constantly replenish the brain with oligodendrocytes, which, in turn, refresh the myelin insulation that helps signals travel faster through the brain. In Huntington’s disease, OPCs are unable to keep up with demand, resulting in deficient myelination in the brain, which can be seen in patients with Huntington’s disease as atrophy of the white matter. When the researchers overexpressed Tcf7l2 in mice with the Huntington’s disease mutation, their OPCs recovered and restored the myelin lost by the disease.
A sister article from the Goldman laboratory, which appeared in Cell reports last year looked at how the genetic defect that lies at the heart of the disease affects the development and function of astrocytes, which support neurons and their synaptic connections. This article has highlighted genetic pathways aligned with Tcf7l2, found in mouse and human Huntington’s astrocytes, which is a major contributor to Huntington’s synaptic dysfunction, which in turn leads to the behavioral and psychiatric symptoms of the disease. . Taken together, these papers provide a clearer picture of the genetic mechanisms by which Huntington’s disease impairs glial cell function and ultimately leads to neurological disability, while providing new cellular and molecular targets for potential treatment.
Researchers believe these findings put new therapies within reach. Replacing or “repairing” faulty glial cells may prove a much easier proposition than replenishing neurons lost in disease. A study from Goldman’s lab in 2018 showed the complexity of the genetic defects of Huntington’s glia and highlighted the utility of replacing diseased cells with healthy ones, an approach the lab had shown effective in mouse models of the disease. disease in a previous study. in 2016. Together, this series of studies laid the groundwork for targeting glial cells for treatment, and potentially outright replacement, in Huntington’s disease.
The other authors of the study are John Mariani, Ashley Tate, Pernille Madsen, Kathleen Clark, Kevin Welle, Renee Solly, Laetitian Capellano, Karen Bentley and Devin Chandler-Militello from URMC. The research was funded with support from the National Institute of Neurological Disorders and Stroke, the Inherited Diseases Foundation, CHDI and Sana Biotechnology.
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