Bioenergetics in fibroblasts of patients with Huntington disease are associated with age at onset.
Bioenergetics in fibroblasts of patients with Huntington disease are associated with age at onset.
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DOI：
10.1212/nxg.0000000000000275
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发表时间：
2018-10
期刊：
影响因子：
--
通讯作者：
Aziz NA
中科院分区：
文献类型：
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作者：
Gardiner SL;Milanese C;Boogaard MW;Buijsen RAM;Hogenboom M;Roos RAC;Mastroberardino PG;van Roon-Mom WMC;Aziz NA
我们的目的是评估来源于亨廷顿病患者的成纤维细胞系的能量代谢差异是否与发病年龄相关，而与突变等位基因中的胞嘧啶-腺嘌呤-鸟嘌呤（CAG）重复数无关。在这项研究中，我们使用莱顿亨廷顿病数据库，选择了9对在突变CAG重复序列大小和性别上匹配的亨廷顿病患者，但发病年龄至少相差10岁。从皮肤活检中，我们分离成纤维细胞，其中我们（1）定量过氧化氢刺激前后的ATP浓度，（2）使用Seahorse XF细胞外通量分析仪XF 24测量线粒体呼吸和糖酵解的真实的时间。成纤维细胞中的ATP浓度显着较低的亨廷顿病患者的发病年龄较早，独立的日历年龄和疾病的持续时间。最大呼吸，备用容量，呼吸依赖于复合物II活性，线粒体呼吸指数显着降低亨廷顿病患者发病年龄较早，再次独立的日历年龄和疾病持续时间。一个效率较低的生物能量学档案被发现在成纤维细胞与亨廷顿病患者的发病年龄较早独立的突变CAG重复序列大小。因此，生物能量学的差异可以部分解释亨廷顿病发病年龄的剩余变化。
We aimed to assess whether differences in energy metabolism in fibroblast cell lines derived from patients with Huntington disease were associated with age at onset independent of the cytosine-adenine-guanine (CAG) repeat number in the mutant allele. For this study, we selected 9 pairs of patients with Huntington disease matched for mutant CAG repeat size and sex, but with a difference of at least 10 years in age at onset, using the Leiden Huntington disease database. From skin biopsies, we isolated fibroblasts in which we (1) quantified the ATP concentration before and after a hydrogen-peroxide challenge and (2) measured mitochondrial respiration and glycolysis in real time, using the Seahorse XF Extracellular Flux Analyzer XF24. The ATP concentration in fibroblasts was significantly lower in patients with Huntington disease with an earlier age at onset, independent of calendar age and disease duration. Maximal respiration, spare capacity, and respiration dependent on complex II activity, and indices of mitochondrial respiration were significantly lower in patients with Huntington disease with an earlier age at onset, again independent of calendar age and disease duration. A less efficient bioenergetics profile was found in fibroblast cells from patients with Huntington disease with an earlier age at onset independent of mutant CAG repeat size. Thus, differences in bioenergetics could explain part of the residual variation in age at onset in Huntington disease.