Researchers Find Astrocytes to Be Central Driver Behind Huntington Disease Pathology

Currently, a cure does not exist for Huntington disease (HD)—a fatal neurodegenerative disease characterized by loss of voluntary motor control, psychiatric disturbances, and cognitive decline. However, recent study results reveal the importance of the role of astrocytes in the brain due to the exchange between astrocytes and neurons that is disturbed during HD.

“Astrocytes play a crucial role in up-take of the neurotransmitter glutamate and providing neurons with glutamine, an important precursor for glutamate and gamma-aminobutyric acid (GABA) synthesis (called the glutamate-GABA-glutamine cycle),” the study explained.

The study involved a systemwide exploration of protein changes in the 4 brain regions of 12-week-old transgenic R6/2 mice in order to gain a better understanding of the molecular pathogenesis of HD. The researchers applied an unbiased systemwide proteomics strategy that has been used for quantitative brain analyses. Through the use of the strategy, the researchers identified 6801 proteins and quantified their expression changes among the different brain regions.

The strategy also revealed several protein changes in key metabolic pathways, including glycolysis, the tricarboxylic acid (TCA) cycle, and the glutamate-GABA-glutamine cycle. A functional metabolic analysis was conducted on acutely isolated brain slices from the striatum and cortex using stable C-labeled energy substrates coupled to gas chromatography—mass spectrometry analyses.

Overall, the results of the analyses demonstrated that proteins with decreased expression were mostly related to biological processes, such as synapse function and neurotransmitter homeostasis, while proteins with increased expression belonged to other processes, including chromatin regulation and the proteasomal machinery.

Based on the collective results, the study concluded that early alterations in metabolic protein expression may suggest that metabolic deficits could be causal and not just consequences of late-stage disease progression. Specifically, the results indicated that metabolic defects are more prominent in astrocytes compared with neurons in the R6/2 brain and may take place as early as 8 weeks of age.

“Our data suggest that astrocytes could be a central driver behind HD pathology as result of impaired metabolism and glutamine release, leading to diminished neuronal GABA synthesis. This would lead to impaired inhibitory neurotransmission and, in turn, enhance the detrimental excitatory neurotransmission observed in HD,” concluded the researchers. “Hence, our data suggest that normalizing astrocyte metabolism may be a beneficial approach to restore or improve neuronal function in HD.”

The researchers call for functional metabolic follow-up studies at presymptomatic and early stages in order to determine how early astrocytic metabolism is affected.

Reference

Skotte NH, Andersen JV, Santos A, et al. Integrative characterization of the R6/2 mouse model of Huntington's disease reveals dysfunctional astrocyte metabolism. Cell Rep. 2018;23(7):2211-2224. doi: 10.1016/j.celrep.2018.04.052.