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

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.

Changes in mitochondrial function in patients with neuromyelitis optica; correlations with motor and cognitive disabilities

“…After transferring the supernatant into a new tube, samples centrifuged for 10 min (20,000× g, 4˚C). The resulting pellet was re-suspended in icecold 0.2 mM sodium citrate and then sonicated for 20 s [22]. Before the enzymatic assays, the extract was further diluted and protein concentration of samples were determined using Bradford method [21].…”

Knockout of ISCA1 causes early embryonic death in rats

“…The primary activity of ACO2 protein is to control cellular adenosine triphosphate (ATP) production via conversion of citrate to isocitrate . Mutations or altered activity of ACO2 are associated with diseases such as epilepsy, brain atrophy, optic atrophy, retinal degeneration, and Huntington's Disease . Our results showed that ACO2 protein increased by 60% in ISCA1 knockout embryos (Figure A,C), unlike the observed decrease in Fe/S transfer protein.…”

“…Our results showed that ACO2 protein increased by 60% in ISCA1 knockout embryos (Figure A,C), unlike the observed decrease in Fe/S transfer protein. ACO2 is central to carbohydrate and energy metabolism and is associated with multiple metabolic pathways and pathologic conditions such as Huntington's Disease, hypoxia, and reactive oxygen species (ROS) and energy metabolism defects . ACO2 production could be regulated by cell energy metabolism and the observed increase in ACO2 activity might counteract cell energy metabolism defects .…”

Mitochondrial aconitase controls adipogenesis through mediation of cellular ATP production

“…Since then, additional reports described that autosomal recessive Aco2 mutations can cause either isolated or syndromic optic neuropathy 54 . Decreased Aco2 activity was found in the peripheral blood mononuclear cells of both Huntington's disease patients and presymptomatic Huntington's disease mutation carriers 55 . Also, a homozygous missense mutation was identified in the Aco2 gene (c.1240T > G p. Phe414Val) that segregated with hereditary spastic paraplegia complicated by intellectual disability and microcephaly 56 .…”