Department of Neurology, Chang Gung Memorial Hospital, Linkou; Chang-Gung University College of Medicine, Taoyuan 33305, Taiwan.
Int J Mol Sci. 2017 Nov 21;18(11):2480. doi: 10.3390/ijms18112480.
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 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 and R6/2 mice. Aco2 activity was decreased in striatum of Hdh 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, -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.
亨廷顿病（HD）是由不稳定的胞嘧啶腺嘌呤鸟嘌呤（CAG）三核苷酸重复扩展引起的，该扩展在亨廷顿蛋白中编码一个多聚谷氨酰胺片段。以前，我们在 16 个月大的 Hdh 敲入小鼠纹状体中鉴定出几种上调和下调的蛋白质分子，这种小鼠模型模拟了人类 HD 的早期阶段。在这些分子中，位于线粒体基质中的 aconitase 2（Aco2）参与能量生成，并且容易受到增加的氧化应激的影响，这会导致 Aco2 活性失活。在这项研究中，我们证明了 Hdh 和 R6/2 小鼠的大脑中 Aco2 蛋白水平和活性降低。在 16 个月大的 Hdh 小鼠和 7 至 13 周大的 R6/2 小鼠的纹状体中，Aco2 活性降低。R6/2 小鼠纹状体中的 Aco2 活性可以通过抗氧化剂 - 乙酰 - l - 半胱氨酸恢复，支持 HD 中 Aco2 活性降低可能是由于氧化损伤增加所致。在 HD 患者和预症状 HD 突变（PreHD）携带者的外周血单核细胞（PBMC）中进一步发现 Aco2 活性降低，而 PBMC 中的 Aco2 蛋白水平降低仅存在于 HD 患者中。Aco2 活性与运动评分、独立性量表以及统一亨廷顿病评定量表的功能能力以及疾病持续时间显著相关。我们的研究为评估 HD 患者和 PreHD 携带者的疾病状况提供了一个潜在的生物标志物。
