Integrative Characterization of the R6/2 Mouse Model of Huntington's Disease Reveals Dysfunctional Astrocyte Metabolism

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.