TY - JOUR
T1 - Integrative Characterization of the R6/2 Mouse Model of Huntington's Disease Reveals Dysfunctional Astrocyte Metabolism
AU - Skotte, Niels H.
AU - Andersen, Jens V.
AU - Santos, Alberto
AU - Aldana, Blanca I.
AU - Willert, Cecilie W.
AU - Nørremølle, Anne
AU - Waagepetersen, Helle S.
AU - Nielsen, Michael L.
N1 - Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.
PY - 2018/5/15
Y1 - 2018/5/15
N2 - 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. Skotte et al. report that systems-wide analysis of the R6/2 mouse spatial proteome identifies key protein changes related to energy metabolism, synapse function, and neurotransmitter homeostasis. Astrocytic glutamate-GABA-glutamine cycling is compromised, causing impaired glutamine release and, consequently, GABA synthesis. Thus, therapeutic strategies to improve astrocytic glutamine homeostasis may ameliorate symptoms in HD.
AB - 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. Skotte et al. report that systems-wide analysis of the R6/2 mouse spatial proteome identifies key protein changes related to energy metabolism, synapse function, and neurotransmitter homeostasis. Astrocytic glutamate-GABA-glutamine cycling is compromised, causing impaired glutamine release and, consequently, GABA synthesis. Thus, therapeutic strategies to improve astrocytic glutamine homeostasis may ameliorate symptoms in HD.
U2 - 10.1016/j.celrep.2018.04.052
DO - 10.1016/j.celrep.2018.04.052
M3 - Journal article
C2 - 29768217
SN - 2211-1247
VL - 23
SP - 2211
EP - 2224
JO - Cell Reports
JF - Cell Reports
IS - 7
ER -