TY - JOUR
T1 - HACE1 is essential for astrocyte mitochondrial function and influences Huntington disease phenotypes in vivo
AU - Ehrnhoefer, Dagmar E
AU - Southwell, Amber L
AU - Sivasubramanian, Meenalochani
AU - Qiu, Xiaofan
AU - Villanueva, Erika B
AU - Xie, Yuanyun
AU - Waltl, Sabine
AU - Anderson, Lisa
AU - Fazeli, Anita
AU - Casal, Lorenzo
AU - Felczak, Boguslaw
AU - Tsang, Michelle
AU - Hayden, Michael R
N1 - © The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please email: [email protected].
PY - 2018/1/15
Y1 - 2018/1/15
N2 - Oxidative stress is a prominent feature of Huntington disease (HD), and we have shown previously that reduced levels of hace1 (HECT domain and Ankyrin repeat containing E3 ubiquitin protein ligase 1) in patient striatum may contribute to the pathogenesis of HD. Hace1 promotes the stability of Nrf2 and thus plays an important role in antioxidant response mechanisms, which are dysfunctional in HD. Moreover, hace1 overexpression mitigates mutant huntingtin (mHTT)-induced oxidative stress in vitro through promotion of the Nrf2 antioxidant response. Here, we show that the genetic ablation of hace1 in the YAC128 mouse model of HD accelerates motor deficits and exacerbates cognitive and psychiatric phenotypes in vivo. We find that both the expression of mHTT and the ablation of hace1 alone are sufficient to cause deficits in astrocytic mitochondrial respiration. We confirm the crucial role of hace1 in astrocytes in vivo, since its ablation is sufficient to cause dramatic astrogliosis in wild-type FVB/N mice. Astrogliosis is not observed in the presence of mHTT but a strong dysregulation in the expression of astrocytic markers in HACE1-/- x YAC128 striatum suggests an additive effect of mHTT expression and hace1 loss on this cell type. HACE1-/- x YAC128 mice and primary cells derived from these animals therefore provide model systems that will allow for the further dissection of Nrf2 pathways and astrocyte dysfunction in the context of HD.
AB - Oxidative stress is a prominent feature of Huntington disease (HD), and we have shown previously that reduced levels of hace1 (HECT domain and Ankyrin repeat containing E3 ubiquitin protein ligase 1) in patient striatum may contribute to the pathogenesis of HD. Hace1 promotes the stability of Nrf2 and thus plays an important role in antioxidant response mechanisms, which are dysfunctional in HD. Moreover, hace1 overexpression mitigates mutant huntingtin (mHTT)-induced oxidative stress in vitro through promotion of the Nrf2 antioxidant response. Here, we show that the genetic ablation of hace1 in the YAC128 mouse model of HD accelerates motor deficits and exacerbates cognitive and psychiatric phenotypes in vivo. We find that both the expression of mHTT and the ablation of hace1 alone are sufficient to cause deficits in astrocytic mitochondrial respiration. We confirm the crucial role of hace1 in astrocytes in vivo, since its ablation is sufficient to cause dramatic astrogliosis in wild-type FVB/N mice. Astrogliosis is not observed in the presence of mHTT but a strong dysregulation in the expression of astrocytic markers in HACE1-/- x YAC128 striatum suggests an additive effect of mHTT expression and hace1 loss on this cell type. HACE1-/- x YAC128 mice and primary cells derived from these animals therefore provide model systems that will allow for the further dissection of Nrf2 pathways and astrocyte dysfunction in the context of HD.
KW - Animals
KW - Astrocytes/metabolism
KW - Corpus Striatum/metabolism
KW - Disease Models, Animal
KW - Huntington Disease/genetics
KW - Mice
KW - Mitochondria/metabolism
KW - NF-E2-Related Factor 2/metabolism
KW - Neostriatum/metabolism
KW - Nerve Tissue Proteins/metabolism
KW - Oxidative Stress/physiology
KW - Tumor Suppressor Proteins/metabolism
KW - Ubiquitin-Protein Ligases/metabolism
U2 - 10.1093/hmg/ddx394
DO - 10.1093/hmg/ddx394
M3 - Journal article
C2 - 29121340
SN - 0964-6906
VL - 27
SP - 239
EP - 253
JO - Human Molecular Genetics
JF - Human Molecular Genetics
IS - 2
ER -