A mechanistic study on mouse models of Huntington’s disease led by scientists at the University of Rochester Medical Center (URMC) reinforces the potential of therapies that target glia—support cells critical for neuronal health and function in the brain. Myelin-encased neuronal projections make up the outer white matter of the brain. Glial cells called “oligodendroglia” produce this myelin. Defects in the specialization or differentiation of oligodendroglia into mature myelin causes the fatal, hereditary white matter disorder called Huntington’s disease.
However, Huntington’s disease has long been considered a neuronal disease because demyelination leads to the death of medium spiny motor neurons, which is ultimately responsible for the progressive clinical hallmarks of the disease: involuntary movements, impaired motor coordination, cognitive decline, depression, and psychosis.
The new study led by neurologist Steven Goldman, MD, PhD, published in the journal Cell Reports, takes a closer look at the role of defects in oligodendrocyte progenitor cells (OPC) in the maintenance of myelin in adult animal models of Huntington’s disease (“A TCF7L2-responsive suppression of both homeostatic and compensatory remyelination in Huntington disease mice”). OPCs supply the brain with a constant source of oligodendrocytes, which in turn refresh myelin insulations on neurons.
“Huntington’s is a complex disease that impacts both neurons and support cells. To use an analogy, not only is the patient sick, but so are the doctor and the nurse,” said first author Abdellatif Benraiss, PhD, a research associate professor in neurology at URMC. “While the loss of neurons gives rise to the symptoms and the ultimate fatal nature of the disease, reversing glial dysfunction may give us an opportunity to intervene early in the course of the disease, keeping neurons healthy for longer and slowing disease progression.”
Goldman’s lab had previously identified dysfunctions in two sets of glia—astrocytes and oligodendrocytes, in Huntington’s disease models. In the current study, the investigators looked at two animal models of Huntington’s disease—R6/2 and zQ175 mice. Both models exhibited a progressive, age-related loss of myelin compared to control mice. Upon feeding adult mice cuprizone, a toxic copper chelator that induces demyelination, for six weeks, the investigators found R6/2 mice required significantly more time to restore its myelin.
Next, the investigators isolated RNA and protein from OPCs of the corpus callosum, a thick tract of nerve fibers that connects the two hemispheres of the brain. Upon RNA-sequencing and mass spectrometry of callosal OPCs isolated from both R6/2 and zQ175 mice, they found decreased myelin protein expression and downregulation of genes associated with oligodendrocyte differentiation and myelin formation in both models.
Through analyses of genetic networks, the scientists zeroed in on a repressed transcription factor, Tcf7l2, as the key to suppressed oligodendrocyte differentiation and myelin formation in the mouse models. When they overexpressed the Tcf7l2 gene in mice, they rescued the expression levels of myelin and remyelination in R6/2 mice with depleted myelin. Earlier work from Goldman’s lab had identified a conserved set of glial genes and pathways associated with Tcf7l2 and Huntington’s disease in mice and humans.
The authors noted that this causal link between TCF7l2-dependent transcription and the retention of myelin that the current study demonstrates provides an accessible mechanism that can be used to develop glial therapies for patients with Huntington’s disease.