HACE1 is essential for astrocyte mitochondrial function and influences Huntington disease phenotypes in vivo

Dagmar E Ehrnhoefer; Amber L Southwell; Meenalochani Sivasubramanian; Xiaofan Qiu; Erika B Villanueva; Yuanyun Xie; Sabine Waltl; Lisa Anderson; Anita Fazeli; Lorenzo Casal; Boguslaw Felczak; Michelle Tsang; Michael R Hayden

doi:10.1093/hmg/ddx394

HACE1 is essential for astrocyte mitochondrial function and influences Huntington disease phenotypes in vivo

Dagmar E Ehrnhoefer, Amber L Southwell, Meenalochani Sivasubramanian, Xiaofan Qiu, Erika B Villanueva, Yuanyun Xie, Sabine Waltl, Lisa Anderson, Anita Fazeli, Lorenzo Casal, Boguslaw Felczak, Michelle Tsang, Michael R Hayden

8 Citations (Scopus)

Abstract

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.

Original language	English
Journal	Human Molecular Genetics
Volume	27
Issue number	2
Pages (from-to)	239-253
Number of pages	15
ISSN	0964-6906
DOIs	https://doi.org/10.1093/hmg/ddx394
Publication status	Published - 15 Jan 2018
Externally published	Yes

Keywords

Animals
Astrocytes/metabolism
Corpus Striatum/metabolism
Disease Models, Animal
Huntington Disease/genetics
Mice
Mitochondria/metabolism
NF-E2-Related Factor 2/metabolism
Neostriatum/metabolism
Nerve Tissue Proteins/metabolism
Oxidative Stress/physiology
Tumor Suppressor Proteins/metabolism
Ubiquitin-Protein Ligases/metabolism

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Ehrnhoefer, D. E., Southwell, A. L., Sivasubramanian, M., Qiu, X., Villanueva, E. B., Xie, Y., Waltl, S., Anderson, L., Fazeli, A., Casal, L., Felczak, B., Tsang, M., & Hayden, M. R. (2018). HACE1 is essential for astrocyte mitochondrial function and influences Huntington disease phenotypes in vivo. Human Molecular Genetics, 27(2), 239-253. https://doi.org/10.1093/hmg/ddx394

@article{69a96c7e70d446c095432834623d43b1,

title = "HACE1 is essential for astrocyte mitochondrial function and influences Huntington disease phenotypes in vivo",

abstract = "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.",

keywords = "Animals, Astrocytes/metabolism, Corpus Striatum/metabolism, Disease Models, Animal, Huntington Disease/genetics, Mice, Mitochondria/metabolism, NF-E2-Related Factor 2/metabolism, Neostriatum/metabolism, Nerve Tissue Proteins/metabolism, Oxidative Stress/physiology, Tumor Suppressor Proteins/metabolism, Ubiquitin-Protein Ligases/metabolism",

author = "Ehrnhoefer, {Dagmar E} and Southwell, {Amber L} and Meenalochani Sivasubramanian and Xiaofan Qiu and Villanueva, {Erika B} and Yuanyun Xie and Sabine Waltl and Lisa Anderson and Anita Fazeli and Lorenzo Casal and Boguslaw Felczak and Michelle Tsang and Hayden, {Michael R}",

year = "2018",

month = jan,

day = "15",

doi = "10.1093/hmg/ddx394",

language = "English",

volume = "27",

pages = "239--253",

journal = "Human Molecular Genetics",

issn = "0964-6906",

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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

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 -

HACE1 is essential for astrocyte mitochondrial function and influences Huntington disease phenotypes in vivo

Abstract

Keywords

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