Gardiner Sarah L, Milanese Chiara, Boogaard Merel W, Buijsen Ronald A M, Hogenboom Marye, Roos Raymund A C, Mastroberardino Pier G, van Roon-Mom Willeke M C, Aziz N Ahmad
Department of Neurology (S.L.G., M.H., R.A.C.R., N.A.A.), Department of Human Genetic (S.L.G., R.A.M.B., W.M.C.v.R.-M.), and Department of Clinical Genetics (M.W.B.), Leiden University Medical Centre, Leiden; Department of Molecular Genetics (C.M., P.G.M.), Erasmus Medical Centre, Rotterdam, The Netherlands; and German Center for Neurodegenerative Diseases (DZNE) (N.A.A.), Bonn, Germany.
Neurol Genet. 2018 Oct 4;4(5):e275. doi: 10.1212/NXG.0000000000000275. eCollection 2018 Oct.
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.
我们旨在评估亨廷顿病患者来源的成纤维细胞系中能量代谢差异是否与发病年龄相关，且独立于突变等位基因中的胞嘧啶 - 腺嘌呤 - 鸟嘌呤（CAG）重复次数。
在本研究中，我们使用莱顿亨廷顿病数据库，选择了9对亨廷顿病患者，这些患者的突变CAG重复大小和性别相匹配，但发病年龄相差至少10岁。从皮肤活检中，我们分离出成纤维细胞，在这些细胞中我们（1）在过氧化氢刺激前后对ATP浓度进行定量，以及（2）使用海马XF细胞外通量分析仪XF24实时测量线粒体呼吸和糖酵解。
发病年龄较早的亨廷顿病患者的成纤维细胞中的ATP浓度显著较低，这与实际年龄和病程无关。发病年龄较早的亨廷顿病患者的最大呼吸、备用能力、依赖于复合物II活性的呼吸以及线粒体呼吸指标均显著较低，同样与实际年龄和病程无关。
在发病年龄较早的亨廷顿病患者的成纤维细胞中发现了效率较低的生物能量学特征，这与突变CAG重复大小无关。因此，生物能量学差异可以解释亨廷顿病发病年龄的部分残余变异。
