The brain’s support cells show defective development in Huntington’s disease
Confocal image of rat neurons and glia grown in culture and stained with antibodies to microtubule associated protein tau, in green, and glial fibrillary acidic protein (GFAP) in red. Blue is the DNA binding dye DAPI which reveals nuclei. Credit: CC BY-SA 4.0 - GerryShaw
The neurological disorder Huntington’s disease causes behavioral and motor changes, which among other things are a result of dysfunctional maturation or formation of glial cells, the brain’s support cells, according to a new study from the University of Copenhagen.
The brain’s support cells, the so-called glial cells, play a main role in the development of the genetic brain disorder Huntington’s disease, for which there is currently no treatment. In a new study, an international group of researchers from the Faculty of Health and Medical Sciences at the University of Copenhagen, among others, has now mapped important, novel mechanisms in glial cells derived from human embryonic stem cells bearing the Huntington’s disease mutation. The new research results have been published in the prestigious journal Cell Stem Cell.
“In the study, we show that glial cell maturation is severely impaired in patients with Huntington’s disease, and this is a major contributor to the abnormalities we see in the brain. This leads to behavioral changes as well as to changes in motor function. The failure of glial maturation causes many of these symptoms, because diseased glial cells cannot support normal neuronal and synaptic function; this means that the communication between neurons is impaired”, says the last author of the study, Professor Steve Goldman from the Center for Neuroscience at the University of Copenhagen and the Center for Translational Neuromedicine at University of Rochester.
Huntington’s disease is the result of a mutation in a gene – the Huntingtin gene – which codes for a protein that when mutated causes the disease. Huntington’s disease leads to personality changes and a loss in motor coordination. There is currently no treatment that can cure or even slow the disease; at best, physicians can only offer medicines that can alleviate some of its symptoms. The overall goal of Steve Goldman and his research group is to find a meaningful, disease-modifying treatment for the disease.
They have been researching glial cells and degenerative diseases in the brain, including Huntington’s disease, for a number of years, and in this study, they set out to determine what happens to glial cells at the molecular level in the Huntington’s disease brain. To do so the researchers studied mice into which they had transplanted human glial progenitor cells containing the Huntingtin gene. These glial progenitor cells are precursors to mature glial cells and were derived from pluripotent stem cells.
The mice with human glia enabled the researchers to study the development of Huntington disease-derived glial cells. The researchers learned that the maturation of the glia was delayed and abnormal. This led to the production of dysfunctional astrocytes, the most common type of glia in the brain, which regulate the communication between neurons. This poor glial maturation also led to a lack of myelin, the insulating fat that surround the nerve pathways in the brain, and which normally allows and speeds neural communication. The result was a failure of the brain’s white matter in these humanized mouse models of Huntington disease, with its consequent effects on behavior and motor skills. Goldman argues that glial cells are not only important in connection with Huntington’s disease, but also appear to play a main role in several other neurodegenerative and neuropsychiatric diseases, such as schizophrenia.
‘This failure of glial cell maturation appears to be a common element of diseases that involve behavioral abnormalities and psychosis. The unsuccessful glial cell maturation we saw in Huntington’s disease is very similar to what we saw in one of our previous studies, where we studied the role of glial cells in schizophrenia. At the same time, our study stresses the potential of glial cell therapy as a possible treatment for Huntington’s disease and other similar neurodegenerative diseases”, Goldman explains.
Goldman and his colleagues have previously worked with glial cell transplantation, as described in a study from 2016. Here the researchers had transplanted healthy glial cells to mice suffering from Huntington’s disease. This prolonged the life expectancy of the mice and alleviated the symptoms of the disease. And one of the next steps for Goldman and his research group is to conduct clinical trials involving transplantation of healthy glial cells to patients with Huntington’s disease. They hope to be able to launch these trials within the next couple of years.
Materials provided by the University of Copenhagen – Faculty of Health and Medical Sciences. Content may be edited for clarity, style, and length.