HACE1 is Essential for Astrocyte Mitochondrial Function and Influences Huntington Disease Phenotypes in Vivo

Overview

Journal Hum Mol Genet

Specialties Genetics
Molecular Biology

Date 2017 Nov 10

PMID 29121340

Citations 20

Authors

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

Affiliations

Soon will be listed here.

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.

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