Dysfunctional Astrocyte Metabolism Implicated In Huntington's Disease


A previously unknown error in the transport of glutamine between astrocytes and neurons in the brain of mice with Huntington’s disease has been found by researchers from the University of Copenhagen. The researchers believe it is a relevant area on which to focus the effort of developing a future treatment for the disease.

The study describes how the glutamate-GABA-glutamine cycle in the brain is disturbed during Huntington’s disease, highlighting the important role of astrocytes in the brain.

“Researchers used to believe that hereditary diseases—including Huntington’s disease—were primarily a result of problems in the neurons. But here, we show and confirm that the astrocytes also play a main role. Glutamine is produced in the astrocytes and transported to the neurons, where it is used to make neurotransmitters. They are central to the ability to send signals across the brain. If the transport of glutamine from the astrocytes is lost, the neurons stop functioning optimally,"

co-author Niels Henning Skotte said.

900 Protein Alterations

The researchers analysed the protein alterations seen in the four regions of the brain — the striatum, cortex, hippocampus and diencephalon — in mice with advanced Huntington’s disease compared to healthy mice. They found that the striatum, as in humans, was more affected than the other regions of the brain.

They found a total of around 900 protein alterations. This was supported by the researchers’ metabolic studies, which also showed a majority of disorders in the striatum.

The most significant find of the study, according to the researchers, is the reduced exchange of glutamine between astrocytes and neurons. And it is a research area with potential when it comes to future research into whether a normal release of glutamine from the astrocytes can potentially alleviate the symptoms of Huntington’s disease.

“Even though Huntington’s disease is a genetic disease, our study shows a dysregulation of the proteins and the signalling pathways of these proteins. There is currently no cure for Huntington’s disease. But if we were able to find areas in which the effects of the disease may potentially be improved or reduced, it would be a big step in the right direction. This study may provide suggestions for focus areas of future research,"

said Professor Michael Lund Nielsen.

Dysregulated Glutamine Transport

There is currently no cure for the hereditary brain disorder Huntington’s disease, which causes personality alterations and loss of motor control.

More research is required to clarify the role played by dysregulated glutamine transport in the development of Huntington’s disease. However, data suggests that the cycle is disturbed early in the course of the disease.

If this proves correct, it may perhaps play an even greater role in the development of the disease, just as it may potentially increase the chances of alleviating the symptoms, the authors of the study say.

The study was supported in part by the Novo Nordisk Foundation Center for Protein Research, Novo Nordisk Foundation, Danish Council for Independent Research, and the Stadslæge Svend Ahrend Larsen og Grosserer Jon Johannesons Fond.

Skotte, Niels H. et al.
Integrative Characterization of the R6/2 Mouse Model of Huntington’s Disease Reveals Dysfunctional Astrocyte Metabolism
Cell Reports, Volume 23, Issue 7, 2211 – 2224