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Updated: Feb 19, 2026
A Phenotyping Regimen for Genetically Modified Mice Used to Study Genes Implicated in Human Diseases of Aging
Published on: July 14, 2016
HACE1 is essential for astrocyte mitochondrial function and influences Huntington disease phenotypes in vivo
Dagmar E Ehrnhoefer1, Amber L Southwell1, Meenalochani Sivasubramanian1
1Department of Medical Genetics, Centre for Molecular Medicine and Therapeutics (CMMT), CFRI, University of British Columbia, Vancouver, BC V5Z 4H4, Canada.
Insights
Loss of HACE1 (HECT domain and Ankyrin repeat containing E3 ubiquitin protein ligase 1) worsens Huntington disease (HD) symptoms in mice by impairing antioxidant responses and astrocyte function. This highlights HACE1
Area of Science:
- Neuroscience
- Molecular Biology
- Genetics
Background:
- Huntington disease (HD) is characterized by oxidative stress.
- Reduced HECT domain and Ankyrin repeat containing E3 ubiquitin protein ligase 1 (HACE1) levels in the striatum are implicated in HD pathogenesis.
- HACE1 stabilizes Nrf2, a key regulator of antioxidant responses crucial for HD pathology.
Purpose of the Study:
- To investigate the in vivo role of HACE1 in the YAC128 mouse model of Huntington disease.
- To determine the impact of HACE1 deficiency on motor, cognitive, and psychiatric phenotypes in HD.
- To elucidate the role of HACE1 in astrocyte function and mitochondrial respiration in the context of HD.
Main Methods:
- Genetic ablation of HACE1 in the YAC128 mouse model.
- Assessment of motor, cognitive, and psychiatric phenotypes.
- Analysis of astrocytic mitochondrial respiration and astrogliosis.
- Examination of astrocytic marker expression in HACE1-/- x YAC128 mice.
Main Results:
- HACE1 genetic ablation accelerated motor deficits and exacerbated cognitive/psychiatric phenotypes in YAC128 mice.
- Both mutant huntingtin (mHTT) expression and HACE1 ablation impaired astrocytic mitochondrial respiration.
- HACE1 ablation induced significant astrogliosis in wild-type mice.
- A combined effect of mHTT and HACE1 loss on astrocytic marker dysregulation was observed.
Conclusions:
- HACE1 plays a critical role in mitigating HD pathogenesis, particularly in astrocytes.
- HACE1 deficiency exacerbates HD phenotypes by disrupting antioxidant responses and astrocyte mitochondrial function.
- HACE1-/- x YAC128 mice serve as valuable models for studying Nrf2 pathways and astrocyte dysfunction in HD.
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.
