Department of Medical Biochemistry, Institute of Clinical Medicine, University of Oslo, 0372 Oslo, Norway.
Department of Microbiology, Oslo University Hospital, 0372 Oslo, Norway.
Dis Model Mech. 2018 Oct 24;11(10):dmm035949. doi: 10.1242/dmm.035949.
Huntington's disease (HD) is a monogenic, progressive, neurodegenerative disorder with currently no available treatment. The Libechov transgenic minipig model for HD (TgHD) displays neuroanatomical similarities to humans and exhibits slow disease progression, and is therefore more powerful than available mouse models for the development of therapy. The phenotypic characterization of this model is still ongoing, and it is essential to validate biomarkers to monitor disease progression and intervention. In this study, the behavioral phenotype (cognitive, motor and behavior) of the TgHD model was assessed, along with biomarkers for mitochondrial capacity, oxidative stress, DNA integrity and DNA repair at different ages (24, 36 and 48 months), and compared with age-matched controls. The TgHD minipigs showed progressive accumulation of the mutant huntingtin (mHTT) fragment in brain tissue and exhibited locomotor functional decline at 48 months. Interestingly, this neuropathology progressed without any significant age-dependent changes in any of the other biomarkers assessed. Rather, we observed genotype-specific effects on mitochondrial DNA (mtDNA) damage, mtDNA copy number, 8-oxoguanine DNA glycosylase activity and global level of the epigenetic marker 5-methylcytosine that we believe is indicative of a metabolic alteration that manifests in progressive neuropathology. Peripheral blood mononuclear cells (PBMCs) were relatively spared in the TgHD minipig, probably due to the lack of detectable mHTT. Our data demonstrate that neuropathology in the TgHD model has an age of onset of 48 months, and that oxidative damage and electron transport chain impairment represent later states of the disease that are not optimal for assessing interventions.This article has an associated First Person interview with the first author of the paper.
亨廷顿病（HD）是一种单基因、进行性、神经退行性疾病，目前尚无可用的治疗方法。Libechov 转基因小型猪 HD 模型（TgHD）在神经解剖学上与人相似，且疾病进展缓慢，因此比现有的用于开发治疗方法的小鼠模型更具优势。该模型的表型特征仍在进行中，验证生物标志物以监测疾病进展和干预至关重要。在这项研究中，评估了 TgHD 模型的行为表型（认知、运动和行为），以及不同年龄（24、36 和 48 个月）的线粒体容量、氧化应激、DNA 完整性和 DNA 修复的生物标志物，并与年龄匹配的对照组进行了比较。TgHD 小型猪的脑组织中逐渐积累突变型亨廷顿蛋白（mHTT）片段，并在 48 个月时表现出运动功能下降。有趣的是，这种神经病理学进展没有任何其他评估的生物标志物发生显著的年龄依赖性变化。相反，我们观察到了与基因型特异性相关的线粒体 DNA（mtDNA）损伤、mtDNA 拷贝数、8-氧鸟嘌呤 DNA 糖基化酶活性和全局水平的表观遗传标记 5-甲基胞嘧啶的变化，我们认为这表明存在一种代谢改变，这种改变表现在进行性神经病理学中。TgHD 小型猪的外周血单核细胞（PBMC）相对未受影响，可能是因为检测不到 mHTT。我们的数据表明，TgHD 模型的神经病理学发病年龄为 48 个月，氧化损伤和电子传递链损伤代表疾病的晚期状态，不适合评估干预措施。本文有一篇相关的第一人称采访，采访对象是该论文的第一作者。
