Summary: Researchers have identified a reduced exchange of glutamine between astrocytes and neurons in a new Huntington’s disease study.
Source: University of Copenhagen.
In a new study, researchers from the University of Copenhagen have discovered a hitherto unknown error in the transport of glutamine between astrocytes and neurons in the brain of mice with Huntington’s disease. At the same time, it is a relevant area on which to focus the effort of developing a future treatment for the disease, the researchers believe.
There is currently no cure for the hereditary brain disorder Huntington’s disease, which causes personality alterations and loss of motor control. But now researchers have come one step closer to uncovering what actually happens in the brain of Huntington’s patients. In a new study, researchers from the Novo Nordisk Foundation Center for Protein Research and the Department of Drug Design and Pharmacology at the University of Copenhagen have discovered a hitherto unknown error in the transport of glutamine in the brain of mice suffering from Huntington’s disease.
The study, which has been published in the scientific journal Cell Reports, describes how an important exchange between astrocytes and neurons in the brain is disturbed during Huntington’s disease – more precisely, the glutamate-GABA-glutamine cycle. According to the researchers, this highlights 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’, says Postdoc and First Author of the Study Niels Henning Skotte.
Huntington’s Above All Affects the Striatum
The researchers have analysed the protein alterations seen in the four regions of the brain – striatum, cortex, hippocampus and diencephalon – in mice with advanced Huntington’s disease compared to healthy mice. Here 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 important 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’, says Professor Michael Lund Nielsen.
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.
About Huntington’s disease:
* Huntington’s disease was first described in 1872 by the American doctor George Huntington, after whom the disease was named.
* The disease is caused by a mutation in a specific gene – the so-called huntingtin gene. The gene codes for a protein, which causes the disease. The researchers still do not know exactly which function the protein performs and which biological processes it affects.
* Huntington’s disease is a hereditary disease, and persons suffering from Huntington’s have a 50-per cent risk of passing the gene on to their children.
* In Denmark 350-400 persons suffer from Huntington’s disease. The number of people who have the gene, but in whom the disease has not developed yet is believed to be higher, though.
* Huntington’s disease generally begins to manifest itself at the age of 30-50 years. It may also develop earlier and later in life, though. Symptoms may vary from person to person and include alterations of personality and intellect as well as motor dysfunctions.
* There is currently no treatment for curing or inhibiting the disease, only drugs capable in some cases of suppressing or alleviating the symptoms.
Funding: The study is funded by the Novo Nordisk Foundation, the Independent Research Fund Denmark, Stadslæge Svend Ahrend Larsen and Grosserer Jon Johannesons Foundation, and Peter and Emma Thomsen’s Scholarship.
Source: Michael Lund Nielsen – University of Copenhagen Publisher: Organized by NeuroscienceNews.com. Image Source: NeuroscienceNews.com image is adapted from the University of Copenhagen news release. Original Research: Open access research for “Integrative Characterization of the R6/2 Mouse Model of Huntington’s Disease Reveals Dysfunctional Astrocyte Metabolism” by Niels H. Skotte, Jens V. Andersen, Alberto Santos, Blanca I. Aldana, Cecilie W. Willert, Anne Nørremølle, Helle S. Waagepetersen, and Michael L. Nielsen in Cell Reports. Published May 15 2018 doi:10.1016/j.celrep.2018.04.052
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[cbtabs][cbtab title=”MLA”]University of Copenhagen “Important New Piece in Huntington’s Disease Puzzle Identified.” NeuroscienceNews. NeuroscienceNews, 20 June 2018. <https://neurosciencenews.com/glutamine-astrocytes-huntingtons-9388/>.[/cbtab][cbtab title=”APA”]University of Copenhagen (2018, June 20). Important New Piece in Huntington’s Disease Puzzle Identified. NeuroscienceNews. Retrieved June 20, 2018 from https://neurosciencenews.com/glutamine-astrocytes-huntingtons-9388/[/cbtab][cbtab title=”Chicago”]University of Copenhagen “Important New Piece in Huntington’s Disease Puzzle Identified.” https://neurosciencenews.com/glutamine-astrocytes-huntingtons-9388/ (accessed June 20, 2018).[/cbtab][/cbtabs]
Integrative Characterization of the R6/2 Mouse Model of Huntington’s Disease Reveals Dysfunctional Astrocyte Metabolism
Highlights •Spatial brain proteome in R6/2 mouse model is compromised at multiple pathways •Impaired synapse energy metabolism and neurotransmitter homeostasis in R6/2 mice •Decreased astrocytic glutamine release in R6/2 mice results in lower GABA labeling
Summary Huntington’s disease is a fatal neurodegenerative disease, where dysfunction and loss of striatal and cortical neurons are central to the pathogenesis of the disease. Here, we integrated quantitative studies to investigate the underlying mechanisms behind HD pathology in a systems-wide manner. To this end, we used state-of-the-art mass spectrometry to establish a spatial brain proteome from late-stage R6/2 mice and compared this with wild-type littermates. We observed altered expression of proteins in pathways related to energy metabolism, synapse function, and neurotransmitter homeostasis. To support these findings, metabolic 13C labeling studies confirmed a compromised astrocytic metabolism and regulation of glutamate-GABA-glutamine cycling, resulting in impaired release of glutamine and GABA synthesis. In recent years, increasing attention has been focused on the role of astrocytes in HD, and our data support that therapeutic strategies to improve astrocytic glutamine homeostasis may help ameliorate symptoms in HD.