Altered Aconitase 2 Activity in Huntington's Disease Peripheral Blood Cells and Mouse Model Striatum.

Chiung-Mei Chen,Yih-Ru Wu,Kuo-Hsuan Chang

doi:10.3390/ijms18112480

Abstract

Huntington’s disease (HD) is caused by an unstable cytosine adenine guanine (CAG) trinucleotide repeat expansion encoding a polyglutamine tract in the huntingtin protein. Previously, we identified several up- and down-regulated protein molecules in the striatum of the Hdh(CAG)150 knock-in mice at 16 months of age, a mouse model which is modeling the early human HD stage. Among those molecules, aconitase 2 (Aco2) located in the mitochondrial matrix is involved in the energy generation and susceptible to increased oxidative stress that would lead to inactivation of Aco2 activity. In this study, we demonstrate decreased Aco2 protein level and activity in the brain of both Hdh(CAG)150 and R6/2 mice. Aco2 activity was decreased in striatum of Hdh(CAG)150 mice at 16 months of age as well as R6/2 mice at 7 to 13 weeks of age. Aco2 activity in the striatum of R6/2 mice could be restored by the anti-oxidant, N-acetyl-l-cysteine, supporting that decreased Aco2 activity in HD is probably caused by increased oxidative damage. Decreased Aco2 activity was further found in the peripheral blood mononuclear cells (PBMC) of both HD patients and pre-symptomatic HD mutation (PreHD) carriers, while the decreased Aco2 protein level of PBMC was only present in HD patients. Aco2 activity correlated significantly with motor score, independence scale, and functional capacity of the Unified Huntington’s Disease Rating Scale as well as disease duration. Our study provides a potential biomarker to assess the disease status of HD patients and PreHD carriers.

Highlights

Huntington’s disease (HD), an autosomal-dominant neurodegenerative disorder, is mainly characterized by different psychiatric symptoms, progressive mental decline and chorea
We examined the effect of NAC on the rotarod performance, body blood sugar, Htt aggregates, and striatal aconitase 2 (Aco2) activity of R6/2 mice
Decreased Aco2 activity and protein levels have been respectively shown in the striatum of R6/2 mice in the late disease stage [19,29], the present study demonstrates that decreased Aco2 activity in R6/2 occurred before overt phenotype manifested

Summary

Introduction

Huntington’s disease (HD), an autosomal-dominant neurodegenerative disorder, is mainly characterized by different psychiatric symptoms, progressive mental decline and chorea. The genetic mutation of HD is an expanded cytosine adenine guanine (CAG) trinucleotide repeat that encodes a polyglutamine (polyQ) tract in the huntingtin (Htt) protein [1]. The polyQ expansion causes a conformational change in the Htt which tends to form intranuclear and cytoplasmic aggregates of affected neurons, which would lead to progressive neuronal dysfunctions [2,3]. While many pathogenic pathways have been uncovered, therapeutic strategies that prevent HD progression or modify disease course are not available yet. Many potential treatments have been reported in cell and/or animal models, but none of them proves to be effective in clinical trials. One of the major drawbacks of the clinical trial for HD treatments is the lack of a useful biomarker that can be used to test the therapeutic efficacy

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