小儿亨廷顿病脑皮质和成纤维细胞中 GLUT-1 的变化：一项观察性病例对照研究。

GLUT-1 changes in paediatric Huntington disease brain cortex and fibroblasts: an observational case-control study.

机构信息

Department of Biochemical Sciences, Sapienza University of Rome, Rome 00185, Italy.

Department of Neurology, Leiden University Medical Centre, ZA Leiden 2311, the Netherlands.

出版信息

EBioMedicine. 2023 Nov;97:104849. doi: 10.1016/j.ebiom.2023.104849. Epub 2023 Oct 26.

DOI:10.1016/j.ebiom.2023.104849

PMID:37898095

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10630613/

Abstract

BACKGROUND

Paediatric Huntington disease with highly expanded mutations (HE-PHD; >80 CAG repeats) presents atypically, compared to adult-onset Huntington disease (AOHD), with neurodevelopmental delay, epilepsy, abnormal brain glucose metabolism, early striatal damage, and reduced lifespan. Since genetic GLUT-1 deficiency syndrome shows a symptom spectrum similar to HE-PHD, we investigated the potential role of the two main glucose transporters, GLUT-1 and GLUT-3, in HE-PHD.

METHODS

We compared GLUT-1 and GLUT-3 protein expression in HE-PHD, juvenile-onset (JOHD), and AOHD brains (n = 2; n = 3; n = 6) and periphery (n = 3; n = 2; n = 2) versus healthy adult controls (n = 6; n = 6). We also investigated mitochondrial complexes and hexokinase-II protein expression.

FINDINGS

GLUT-1 and GLUT-3 expression were significantly lower in HE-PHD frontal cortex (p = 0.009, 95% [CI 13.4, 14.7]; p = 0.017, 95% [CI 14.2, 14.5]) versus controls. In fibroblasts, GLUT-1 and GLUT-3 expression were lower compared to controls (p < 0.0001, 95% [CI 0.91, 1.09]; p = 0.046, 95% [CI 0.93, 1.07]). In the frontal cortex, this occurred without evidence of extensive neuronal degeneration. Patients with HE-PHD had deregulated mitochondrial complex expression, particularly complexes II-III, levels of which were lower in frontal cortex versus controls (p = 0.027, 95% [CI 17.1, 17.6]; p = 0.002, 95% CI [16.6, 16.9]) and patients with AOHD (p = 0.052, 95% [CI 17.0, 17.6]; p = 0.002, 95% [CI 16.6, 16.7]). Hexokinase-II expression was also lower in HE-PHD frontal cortex and striatum versus controls (p = 0.010, 95% [CI 17.8, 18.2]; p = 0.045, 95% [CI 18.6, 18.7]) and in frontal cortex versus patients with AOHD (p = 0.013, 95% [CI 17.7, 18.1]). Expression JOHD levels were consistently different to those of HE-PHD but similar to those of AOHD.

INTERPRETATION

Our data suggest a dysfunctional hypometabolic state occurring specifically in paediatric Huntington disease brains.

FUNDING

'5 × 1000' Personal Income Tax donation to LIRH Foundation; Italian Ministry of HealthRC2301MH04 and RF-2016-02364123 to CSS.

摘要

背景

与成人发病的亨廷顿病（AOHD）相比，具有高度扩展突变（HE-PHD；>80 CAG 重复）的儿科亨廷顿病（PHD）表现出神经发育迟缓、癫痫、异常脑葡萄糖代谢、早期纹状体损伤和寿命缩短等非典型特征。由于葡萄糖转运蛋白 1 缺乏症（GLUT-1 deficiency syndrome）表现出与 HE-PHD 相似的症状谱，因此我们研究了两种主要的葡萄糖转运蛋白 GLUT-1 和 GLUT-3 在 HE-PHD 中的潜在作用。

方法

我们比较了 HE-PHD、青少年发病（JOHD）和 AOHD 大脑（n=2；n=3；n=6）和外周组织（n=3；n=2；n=2）与健康成人对照组（n=6；n=6）中的 GLUT-1 和 GLUT-3 蛋白表达。我们还研究了线粒体复合物和己糖激酶-II 蛋白表达。

结果

HE-PHD 额叶皮层的 GLUT-1 和 GLUT-3 表达显著低于对照组（p=0.009，95%[置信区间 13.4，14.7]；p=0.017，95%[置信区间 14.2，14.5]）。在成纤维细胞中，GLUT-1 和 GLUT-3 的表达也低于对照组（p<0.0001，95%[置信区间 0.91，1.09]；p=0.046，95%[置信区间 0.93，1.07]）。在额叶皮层中，这种情况没有证据表明存在广泛的神经元变性。HE-PHD 患者的线粒体复合物表达失调，特别是复合物 II-III，其水平在额叶皮层中低于对照组（p=0.027，95%[置信区间 17.1，17.6]；p=0.002，95%CI[16.6，16.9]）和 AOHD 患者（p=0.052，95%[置信区间 17.0，17.6]；p=0.002，95%CI[16.6，16.7]）。HE-PHD 额叶皮层和纹状体中的己糖激酶-II 表达也低于对照组（p=0.010，95%[置信区间 17.8，18.2]；p=0.045，95%[置信区间 18.6，18.7]）和 AOHD 患者（p=0.013，95%[置信区间 17.7，18.1]）。JOHD 的表达水平与 HE-PHD 不同，但与 AOHD 相似。